2-azabicyclo[3.1.0]hexan-3-one derivatives and methods of use

ABSTRACT

The invention relates to compounds of formula (I): 
                         
wherein Q, A 1 , A 2 , A 3 , A 5 , A 6 , A 7 , A 8 , R 4a , R 4b  and R 5  are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or over-activation of NF-kB signaling is observed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/EP2017/071264, filed Aug. 23, 2017, which claims priority to U.S.Provisional Patent Application No. 62/379,192, filed Aug. 24, 2016, thedisclosures of each of which are incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to2-azabicyclo[3.1.0]hexan-3-one compounds that are inhibitors ofNF-kB-inducing kinase (NIK) useful for treating cancer, fibroticconditions, inflammatory diseases and other conditions responsive to NIKinhibition.

BACKGROUND OF THE INVENTION

NF-kB inducing kinase (NIK) is also known as MAPK kinase kinase 14(MAP3K14) and is a serine/threonine kinase and a member of the MAPKfamily. It was originally identified in a two-hybrid screen as a bindingpartner of TNF receptor (TNFR) associated factor 2 (TRAF2), see,Malinin, N L, et al., Nature, 1997, 385:540-4. Overexpression of NIKleads to the activation of NF-kB and dominant negative forms of NIKlacking kinase activity were able to inhibit NF-kB activation inresponse to TNF and IL-1 treatment. Thus, NIK has been identified as animportant component of the NF-kB signaling pathway. Scientific researchhas shown that blocking the NF-kB signaling pathway in cancer cells cancause such cells to stop proliferating, to die, or to become moresensitive to the action of other anti-cancer therapies. Additionally,NIK is required for non-canonical NF-kB signaling downstream of TNFRSFreceptors which play a role in many inflammatory conditions, such aslupus (including systemic lupus erythematosus), rheumatoid arthritis,inflammatory bowel disease, arthritis, sepsis, gastritis and asthma,among others. Accordingly, organic compounds capable of inhibiting NIKand thereby inhibiting, weakening or lessening the undesired orover-activation of the NF-kB signaling pathway can have a therapeuticbenefit for the treatment diseases and disorders for which suchundesired or over-activation of NF-kB signaling is observed.

2-Azabicyclo[3.1.0]Hexan-3-One Derivatives and Methods of Use BRIEFSUMMARY OF THE INVENTION

Disclosed are 4-alkynyl-4-hydroxy-2-azabicyclo[3.1.0]hexan-3-onecompounds that are inhibitors of NIK kinase, compositions containing oneor more of these compounds and methods for treating diseases mediated byNIK kinase such as cancer and inflammatory diseases.

In one aspect, provided is a compound of formula (I):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:

ring A is a monocycle or a fused bicycle;

Q is N or C, wherein when Q is N, then the bond between A₁ and Q is nota double bond and the bond between Q and A₄ is not a double bond;

A₁ is NR¹, N, S, CR¹ or CHR¹;

A₂ is NR², N, O, S, CR² or CHR²;

A₃ is N or C;

A₄ is N;

provided that no more than two of (i)-(iii) apply: (i) A₁ is NR¹ or N,(ii) A₂ is NR² or N, and (iii) A₃ is N;

each R¹ is independently selected from the group consisting of H,halogen, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), —NHS(O)₂—C₁-C₃ alkyl, C₁-C₃alkyl, C₃-C₇ cycloalkyl, C₁-C₃ alkoxy and 3-11 membered heterocyclyl,wherein the C₁-C₃ alkyl of R¹ is optionally substituted by F, OH, CN,SH, C₁-C₃ alkoxy or 3-11 membered heterocyclyl; the C₃-C₇ cycloalkyl ofR¹ is optionally substituted by F, OH, CN, SH, CH₃ or CF₃; the C₁-C₃alkoxy of R¹ is optionally substituted by F, OH, CN or SH; and the 3-11membered heterocyclyl of R¹ is optionally substituted by F, OH, CN, SH,CF₃ or C₁-C₃ alkyl,

each R² is independently selected from the group consisting of H,NR^(a)R^(b), C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, phenyl and3-11 membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₁-C₆ alkoxy, phenyl and 3-11 membered heterocyclyl of R² is optionallysubstituted by R^(c); or

-   -   R¹ and R² are taken together with the atoms to which they are        attached to form a cyclic group selected from the group        consisting of C₃-C₇ cycloalkyl, phenyl and 3-11 membered        heterocyclyl, wherein the cyclic group is optionally substituted        by R^(d);

each R^(4a) and R^(4b) is independently H or F;

R⁵ is C₁-C₆ alkyl or C₃-C₄ cycloalkyl, wherein the C₁-C₆ alkyl and C₃-C₄cycloalkyl of R⁵ are independently optionally substituted by halogen,OH, or C₁-C₆ alkoxy;

each A₅, A₆, A₇ and A₈ is independently N or CR⁶, provided that at leastthree of A₅, A₆, A₇ and A₈ are independently CR⁶;

each R⁶ is independently selected from the group consisting of H, F, Cl,NH₂, NHCH₃, N(CH₃)₂, OH, OCH₃, OCHF₂, OCH₂F, OCF₃, SH, SCH₃, SCHF₂,SCH₂F, CN, CH₃, CHF₂, CH₂F, CH₂OH, CF₃, NO₂ and N₃;

R^(a) is selected from the group consisting of H and C₁-C₆ alkyloptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃;

R^(b) is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₆ cycloalkyl, C(O)R^(g), phenyl and 3-11 memberedheterocyclyl wherein R^(b) may be optionally substituted by C₁-C₃alkoxy, F, OH, CN, SH, CH₃ or CF₃;

R^(c) and R^(d) are each independently selected from the groupconsisting of halogen, —(X¹)₀₋₁—CN, —(X¹)₀₋₁—NO₂, —(X¹)₀₋₁—SF₅,—(X¹)₀₋₁—OH, —(X¹)₀₋₁—NH₂, —(X¹)₀₋₁—N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))(R^(1a)), —(X¹)₀₋₁—CF₃, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, oxo, —(X¹)₀₋₁—C₁-C₆alkyl, —(X¹)₀₋₁—C₃-C₁₀ cycloalkyl, —O—C₃-C₁₀ cycloalkyl, —(X¹)₀₋₁-3-11membered heterocyclyl, —(X¹)₀₋₁—C₆-C₁₀ aryl, —C(═O)(X¹)₀₋₁—C₃-C₁₀cycloalkyl, —C(═O)(X¹)₀₋₁-3-11 membered heterocyclyl,—(X¹)₀₋₁—C(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—C(═Y¹)NH₂,—(X¹)₀₋₁—C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—C(═Y¹)OR^(1a),—(X¹)₀₋₁—C(═Y¹)OH, —(X¹)₀₋₁—N(H)C(═Y¹)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))C(═Y¹)(R^(1a)), —(X¹)₀₋₁—N(R^(1b))C(═Y¹)(H),—(X¹)₀₋₁—N(H)C(═Y¹)OR^(1a), —(X¹)₀₋₁—N(R^(1b))C(═Y¹)OR^(1a),—(X¹)₀₋₁—S(O)₁₋₂R^(1a), —(X¹)₀₋₁—N(H)S(O)₁₋₂R^(1a),—(X¹)₀₋₁—N(R^(1b))S(O)₁₋₂R^(1a), —(X¹)₀₋₁—S(O)₀₋₁N(H)(R^(1a)),—(X¹)₀₋₁—S(O)₀₋₁N(R^(1b))(R^(1a)), —(X¹)₀₋₁—S(O)₀₋₁NH₂,—(X¹)₀₋₁—S(═O)(═NR^(1b))R^(1a), —(X¹)₀₋₁—C(═Y¹)R^(1a), —(X¹)₀₋₁—C(═Y¹)H,—(X¹)₀₋₁—C(═NOH)R^(1a), —(X¹)₀₋₁—C(═NOR^(1b))R^(1a),—(X¹)₀₋₁—NHC(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—NHC(═Y¹)NH₂,—(X¹)₀₋₁—NHC(═Y¹)N(R^(1b))(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—N(R^(1a))C(═Y¹)NH₂,—(X¹)₀₋₁—OC(═Y¹)R^(1a), —(X¹)₀₋₁—OC(═Y¹)H, —(X¹)₀₋₁—OC(═Y)OR^(1a),—(X¹)₀₋₁—OP(═Y¹)(OR^(1a))(OR^(1b)), —(X¹)—SC(═Y¹)OR^(1a) and—(X¹)—SC(═Y¹)N(R^(1a))(R^(1b)); wherein X¹ is selected from the groupconsisting of C₁-C₆ alkylene, C₁-C₆ heteroalkylene, C₂-C₆ alkenylene,C₂-C₆ alkynylene, C₁-C₆ alkyleneoxy, C₃-C₇ cycloalkylene, 3-11 memberedheterocyclylene and phenylene; R^(1a) and R^(1b) are each independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkylene)C₁-C₆ alkyl,3-11 membered heterocyclyl, (3-11 membered heterocyclylene)C₁-C₆ alkyl,phenyl, and (C₆-C₁₀ arylene)C₁-C₆ alkyl, or R^(1a) and R^(1b), whenattached to the same nitrogen atom, are taken together with the nitrogento which they are attached to form a 3-11 membered heterocyclylcomprising 0-3 additional heteroatoms selected from N, O and S; Y¹ is O,NR^(1c) or S wherein R^(1c) is H or C₁-C₆ alkyl; wherein any portion ofan R^(c) or R^(d) substituent, including R^(1a), R^(1b) and R^(1c), ateach occurrence is independently further substituted by from 0 to 4R^(f) substituents selected from the group consisting of halogen, CN,NO₂, SF₅, OH, NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), oxo, C₁-C₆ alkyl,—(C₂-C₆ alkynylene)-(3-11 membered heterocyclyl, wherein theheterocyclyl is optionally substituted by R^(e)), C₁-C₆ hydroxyalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl, 3-11membered heterocyclyl, —C(═O)N(H)(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—C(═O)NH₂, —C(═O)OC₁-C₆ alkyl, —C(═O)OH, —N(H)C(═O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(═O)(C₁-C₆ alkyl), —N(H)C(═O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(═O)OC₁-C₆ (halo)alkyl, —S(O)₁₋₂C₁-C₆ alkyl, —N(H)S(O)₁₋₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₁₋₂C₁-C₆ alkyl, —S(O)₀₋₁N(H)(C₁-C₆ alkyl),—S(O)₀₋₁N(C₁-C₆ alkyl)₂, —S(O)₀₋₁NH₂, —C(═O)C₁-C₆ alkyl, —C(═O)C₃-C₇cycloalkyl, —C(═NOH)C₁-C₆ alkyl, —C(═NOC₁-C₆ alkyl)C₁-C₆ alkyl,—NHC(═O)N(H)(C₁-C₆ alkyl), —NHC(═O)N(C₁-C₆ alkyl)₂, —NHC(═O)NH₂,—N(C₁-C₆ alkyl)C(═O)N(H)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(═O)NH₂,—OC(═O)C₁-C₆ alkyl, —OC(═O)OC₁-C₆ alkyl, —OP(═O)(OC₁-C₆ alkyl)₂,—SC(═O)OC₁-C₆ alkyl and —SC(═O)N(C₁-C₆ alkyl)₂, wherein any alkylportion of R^(f) is optionally substituted with halogen;

R^(e) is selected from the group consisting of halogen, OH, C₁-C₆ alkyland oxo; and

R^(g) is selected from the group consisting of C₁-C₆ alkyl and C₃-C₆cycloalkyl wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl of R^(g) may beoptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃.

In some embodiments, Q is C, and the compound is of the formula (II):

wherein ring A, A₁, A₂, A₃, A₅, A₆, A₇, A₈, R^(4a), R^(4b) and R⁵ are asdefined for formula (I).

In some embodiments, ring B is a substituted phenyl and Q is C; and thecompound is of the formula (A):

wherein ring A, A₁, A₂, A₃, R^(4a), R^(4b) and R⁵ are as defined forformula (I), n is 0, 1 or 2, and each R⁶ is independently selected fromthe group consisting of F, Cl, OCH₃, CH₃ and CF₃.

In one aspect, provided is a compound of formula (C):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:

ring A is a monocycle or a fused bicycle;

A₁ is NR¹ or CR¹;

A₂ is NR², S or CR²;

A₃ is N or C;

provided that no more than one of (i)-(iii) applies: (i) A₁ is NR¹, (ii)A₂ is NR², and (iii) A₃ is N;

each R¹ is independently —NR^(a)R^(b); C₁-C₃ alkyl optionallysubstituted by F, OH, CN, SH or C₁-C₃ alkoxy; or taken together with R²,where present, and the atoms to which they are attached to form a6-membered heterocyclyl optionally substituted by R^(d);

each R² is independently absent or taken together with R¹ and the atomsto which they are attached to form a 6-membered heterocyclyl optionallysubstituted by R^(d);

n is 0 or 1;

R⁶, where present, is halo;

each R^(a) and R^(b) is independently selected from the group consistingof H and C₁-C₆ alkyl; and

each R^(d) is independently selected from the group consisting of C₁-C₆alkyl optionally substituted by halogen and C₁-C₆ alkoxy optionallysubstituted by halogen.

Provided is a compound of the formula (I), (II), (A), (Aa), (Aa-1),(Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da),(Da-1) or (Da-2), or any variation thereof described herein, or astereoisomer, tautomer, solvate, prodrug or salt thereof. In someembodiments, provided is a compound formula (I), or any variationthereof, or a stereoisomer, tautomer, or salt thereof (e.g., apharmaceutically acceptable salt thereof).

Also provided is a pharmaceutical composition comprising a compound ofthe formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1),(Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) or (Da-2), or anyvariation thereof, and a pharmaceutically acceptable carrier, diluent orexcipient.

In another aspect, provided is a compound of the formula (I), (II), (A),(Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1),(Ca-2), (D), (Da), (Da-1) or (Da-2), or any variation thereof, orpharmaceutical compositions thereof for use in therapy.

Further provided is a compound of the formula (I), (II), (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1) or (Da-2), or any variation thereof, or pharmaceuticalcompositions thereof for use in the treatment of diseases and disorders,including, cancer, fibrotic condition, inflammatory conditions, andautoimmune diseases, among others.

Also provided is use of a compound of the formula (I), (II), (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1) or (Da-2), or any variation thereof, in thepreparation of a medicament for the treatment of diseases and disorders,including, cancer, fibrotic condition, inflammatory conditions, andautoimmune diseases, among others.

In another aspect, provided is a method for treating a disease ordisorder, for example, a cancer, a fibrotic condition, an inflammatorycondition, or an autoimmune disease, in a patient, comprisingadministering to the patient an effective amount of a compound of theformula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2),(C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) or (Da-2), or any variationthereof, or a pharmaceutical composition comprising a compound of theformula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2),(C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) or (Da-2), or any variationthereof.

Further provided is a kit comprising a compound of the formula (I),(II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca),(Ca-1), (Ca-2), (D), (Da), (Da-1) or (Da-2), or any variation thereof.In some embodiments, the kit comprises instructions for use according toa method described herein.

In another aspect, provided is a method of making a compound of theformula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2),(C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) or (Da-2), or any variationthereof. Also provided are compound intermediates useful in synthesis ofa compound of the formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B),(Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) or(Da-2), or any variation thereof.

In one aspect, a variation of a compound is a pharmaceuticallyacceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows human liver microsome clearance (in mL/min/kg) measured forthe exemplary 2-azabicyclo[3.1.0]hexan-3-one compounds in comparisonwith that for the corresponding pyrrolidinone compounds.

FIG. 2 shows human hepatocyte clearance (in mL/min/kg) measured for theexemplary 2-azabicyclo[3.1.0]hexan-3-one compounds in comparison withthat of the corresponding pyrrolidinone compounds.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides, inter alia, compounds of formulae (I), andvariations thereof (such as compounds of formula (II), (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1) or (Da-2), pharmaceutical compositions comprising acompound of formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba),(Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) or (Da-2),and methods of using such compounds and compositions in treatingdiseases and disorders related to undesired or over-activation of theNF-kB signaling pathway, such as, for example, a cancer, a fibroticcondition, an inflammatory condition, or an autoimmune disease.

Definition

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical, wherein the alkyl radical may beoptionally substituted independently with one or more substituentsdescribed herein. In one example, the alkyl radical is one to eighteencarbon atoms (C₁-C₁₈). In other examples, the alkyl radical is C₀-C₆,C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, or C₁-C₃. C₀alkyl refers to a bond. Examples of alkyl groups include methyl (Me,—CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃),2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl(s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl and1-octyl. In some embodiments, substituents for “optionally substitutedalkyls” include one to six instances of F, Cl, Br, I, OH, SH, CN, NH₂,NO₂, N₃, COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl,cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl,piperidinyl, piperazinyl, or pyrimidinyl, wherein the alkyl, aryl andheterocyclic portions thereof may be optionally substituted.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 12 carbon atoms, such as 1-8, 1-6 or 1-3 carbon atoms. “Alkenylene”and “alkynylene” refer to the unsaturated forms of “alkylene” havingdouble or triple bonds, respectively, and typically have from 2 to 12carbon atoms, such as 2-8, 2-6 or 2-3 carbon atoms. “Alkylene”,“alkenylene” and “alkynylene” groups may be optionally substituted.

The term “heteroalkyl” refers to a straight or branched chain monovalenthydrocarbon radical, consisting of the stated number of carbon atoms,or, if none are stated, up to 18 carbon atoms, and from one to fiveheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms can optionally be oxidized and thenitrogen heteroatom can optionally be quaternized. In some embodiments,the heteroatom is selected from O, N and S, wherein the nitrogen andsulfur atoms can optionally be oxidized and the nitrogen heteroatom canoptionally be quatemized. The heteroatom(s) can be placed at anyinterior position of the heteroalkyl group, including the position atwhich the alkyl group is attached to the remainder of the molecule(e.g., —O—CH₂—CH₃). Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—CF₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —OCF₃. Up to twoheteroatoms can be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Heteroalkyl groups can be optionally substituted. Insome embodiments, substituents for “optionally substituted heteroalkyls”include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NO₂, N₃,COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl,piperazinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclicportions thereof may be optionally substituted.

The term “heteroalkylene” means a divalent radical derived fromheteroalkyl, as exemplified by —CH₂CH₂SCH₂CH₂, —CH₂SCH₂CH₂NHCH₃ and—OCH₂CH₃. For heteroalkylene groups, heteroatoms can also occupy eitheror both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like). A heteroalkylene groupmay be optionally substituted.

“Cycloalkyl” refers to a non-aromatic, saturated or partiallyunsaturated hydrocarbon ring group wherein the cycloalkyl group may beoptionally substituted with one or more substituents described herein.In one example, the cycloalkyl group is 3 to 12 carbon atoms (C₃-C₁₂).In other examples, cycloalkyl is C₃-C₆, C₃-C₈, C₃-C₁₀ or C₅-C₁₀. Inother examples, the cycloalkyl group, as a monocycle, is C₃-C₈, C₃-C₆ orC₅-C₆. In another example, the cycloalkyl group, as a bicycle, isC₇-C₁₂. In another example, the cycloalkyl group, as a spiro system, isC₅-C₁₂. Examples of monocyclic cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl and cyclododecyl. Exemplary arrangements of bicycliccycloalkyls having 7 to 12 ring atoms include, but are not limited to,[4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridgedbicyclic cycloalkyls include, but are not limited to,bicyclo[4.1.0]heptane, bicycle[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[4.1.0]heptane and bicyclo[3.2.2]nonane.Examples of spiro cycloalkyl include, spiro[2.2]pentane,spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane andspiro[4.5]decane. In some embodiments, substituents for “optionallysubstituted cycloalkyls” include one to four instances of F, Cl, Br, I,OH, SH, CN, NH₂, NO₂, N₃, COOH, methyl, ethyl, propyl, iso-propyl,butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo,trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino,SO, SO₂, phenyl, piperidinyl, piperazinyl, and pyrimidinyl, wherein thealkyl, aryl and heterocyclic portions thereof may be optionallysubstituted.

The term “cycloalkylene” means a divalent radical derived from acycloalkyl group. A cycloalkylene group may be optionally substituted.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” are used interchangeably and refer to any monocyclic,bicyclic, or spiro, saturated or unsaturated, aromatic (heteroaryl) ornon-aromatic (e.g., heterocycloalkyl), ring system, where the ring atomsare carbon, and at least one atom in the ring or ring system is aheteroatom selected from nitrogen, sulfur or oxygen. If any ring atom ofa cyclic system is a heteroatom, that system is a heterocycle,regardless of the point of attachment of the cyclic system to the restof the molecule. In one example, heterocyclyl includes 3-11 ring atoms(“members”, that is, a 3-11 membered heterocycle) and includesmonocycles, bicycles, and spiro ring systems, wherein the ring atoms arecarbon, and at least one atom in the ring or ring system is a heteroatomselected from nitrogen, sulfur or oxygen. In one example, heterocyclylincludes 1 to 4 heteroatoms. In another example, heterocyclyl includes3- to 7-membered monocycles having one or more heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4-to 6-membered monocycles having one or more heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl includes3-membered monocycles. In another example, heterocyclyl includes4-membered monocycles. In another example, heterocyclyl includes5-6-membered monocycles. In one example, the heterocyclyl group includes0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally beoxidized (e.g., NO, SO, SO₂), and any nitrogen heteroatom may optionallybe quatemized (e.g., [NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). In another example,heterocyclyl includes 3- to 9-membered spiro cycles having one or moreheteroatoms selected from nitrogen, sulfur or oxygen. Exampleheterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl,thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl,isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl,hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl,thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl,thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl,diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl,oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclescontaining a sulfur or oxygen atom and one to three nitrogen atoms arethiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide,thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl,oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ringheterocycles containing 2 to 4 nitrogen atoms include imidazolyl, suchas imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocycles arebenzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example6-membered heterocycles contain one to three nitrogen atoms andoptionally a sulfur or oxygen atom, for example pyridyl, such aspyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yland pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, andpyrazinyl. The pyridine N-oxides and pyridazine N-oxides and thepyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the1,3,4-triazin-2-yl groups, are other example heterocycle groups.Heterocycles may be optionally substituted. For example, substituentsfor “optionally substituted heterocycles” include one to six instancesof F, C₁, Br, I, OH, SH, CN, NH₂, NO₂, N₃, COOH, methyl, ethyl, propyl,iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo,trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino,SO, SO₂, phenyl, piperidinyl, piperazinyl, and pyrimidinyl, wherein thealkyl, aryl and heterocyclic portions thereof may be optionallysubstituted.

The term “heterocyclylene” means a divalent radical derived from aheterocyclyl group. A heterocyclylene group may be optionallysubstituted.

“Heteroaryl” refers to any mono-, bi-, or tricyclic ring system where atleast one ring is a 5- or 6-membered aromatic ring containing from 1 to4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in anexample embodiment, at least one heteroatom is nitrogen. See, forexample, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^(th) ed.Table 7-2 [1985]. Included in the definition are any bicyclic groupswhere any of the above heteroaryl rings are fused to an aryl ring,wherein the aryl ring or the heteroaryl ring is joined to the remainderof the molecule. In one embodiment, heteroaryl includes 4-6 memberedmonocyclic aromatic groups where one or more ring atoms is nitrogen,sulfur or oxygen. In another embodiment, heteroaryl includes 5-6membered monocyclic aromatic groups where one or more ring atoms isnitrogen, sulfur or oxygen. Example heteroaryl groups include thienyl,furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl,thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl and purinyl, as well as benzo-fusedderivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl,benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.Heteroaryl groups can be optionally substituted. In some embodiments,substituents for “optionally substituted heteroaryls” include one to sixinstances of F, Cl, Br, I, OH, SH, CN, NH₂, NO₂, N₃, COOH, methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy,ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino,methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperazinyl, andpyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereofmay be optionally substituted.

In particular embodiments, a heterocyclyl group is attached at a carbonatom of the heterocyclyl group. By way of example, carbon bondedheterocyclyl groups include bonding arrangements at position 2, 3, 4, 5,or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine,position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of apyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran,thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4,or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 ofan isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of anaziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3,4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8of an isoquinoline ring.

In certain embodiments, the heterocyclyl group is N-attached. By way ofexample, the nitrogen bonded heterocyclyl or heteroaryl group includebonding arrangements at position 1 of an aziridine, azetidine, pyrrole,pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole,position 2 of an isoindole, or isoindoline, position 4 of a morpholine,and position 9 of a carbazole, or O-carboline.

The term “alkoxy” refers to those alkyl groups attached to the remainderof the molecule via an oxygen atom. Non-limiting examples includemethoxy, ethoxy and propoxy. Alkoxy groups may be optionallysubstituted, such as by halogen.

The term “alkylthio” refers to those alkyl groups attached to theremainder of the molecule via a sulfur atom. Non-limiting examplesinclude —SCH₃, —SCH₂CH₃ and —SCH₂CH₂CH₃. Alkylthio groups may beoptionally substituted, such as by halogen.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. The term “haloalkyl” is meant to include bothan “alkyl” and a “haloalkyl” substituent. Additionally, the term“haloalkyl,” is meant to include monohaloalkyl and polyhaloalkyl.

The term “oxo” refers to ═O or (═O)₂.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon ring radical, which can be a single ringor multiple rings (up to three rings) which are fused together andhaving the stated number of aryl ring atoms. An aryl group can beoptionally substituted.

A “phenylene” group refers to a divalent radical derived from a phenylgroup. A phenylene group may be optionally substituted.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4,or 5 or more) of the substituents listed for that group in which saidsubstituents may be the same or different. That is, an optionallysubstituted substituent is independent at each occurrence. In anembodiment an optionally substituted group has 1 substituent. In anotherembodiment an optionally substituted group has 2 substituents. Inanother embodiment an optionally substituted group has 3 substituents.In another embodiment an optionally substituted group has 4substituents.

Optional substituents for alkyl and cycloalkyl can be a variety ofgroups including, but not limited to, halogen, oxo, CN, NO₂, N₃, OR′,perfluoro-C₁₋₄ alkoxy, unsubstituted cycloalkyl, unsubstituted aryl(e.g., phenyl), unsubstituted heterocyclyl, NR′R″, SR′, SiR′R″R′″,OC(O)R′, C(O)R′, CO₂R′, CONR′R″, OC(O)NR′R″, NR″C(O)R′, NR′″C(O)NR′R″,NR″C(O)₂R′, S(O)₂R′, S(O)₂NR′R″, NR'S(O)₂R″, NR′″S(O)₂NR′R″, amidino,guanidine, (CH₂)₁₋₄OR′, (CH₂)₁₋₄NR′R″, (CH₂)₁₋₄SR′, (CH₂)₁₋₄SiR′R″R′″,(CH₂)₁₋₄OC(O)R′, (CH₂)₁₋₄C(O)R′, (CH₂)₁₋₄CO₂R′, and (CH₂)₁₋₄CONR′R″, orcombinations thereof, in a number ranging from zero to (2m′+1), where m′is the total number of carbon atoms in such radical. R′, R″ and R′″ eachindependently refer to groups including, for example, hydrogen;unsubstituted C₁₋₆ alkyl; unsubstituted heteroalkyl; unsubstituted aryl;aryl substituted with 1-3 halogens, unsubstituted C₁-C₆ alkyl, C₁-C₆alkoxy or C₁-C₆ thioalkoxy groups, unsubstituted aryl-C₁-C₄ alkylgroups, and unsubstituted heteroaryl. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring atom is optionallysubstituted with N, O or S. For example, NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl.

Similarly, optional substituents for the aryl and heterocyclyl groupsare varied. In some embodiments, substituents for aryl and heterocyclylgroups are selected from the group including, but not limited to,halogen, OR′, OC(O)R′, NR′R″, SR′, R′, CN, NO₂, CO₂R′, CONR′R″, C(O)R′,OC(O)NR′R″, NR″C(O)R′, NR″C(O)₂R′, NR′C(O)NR″R′″, S(O)R′, S(O)₂R′,S(O)₂NR′R″, NR'S(O)₂R″, N₃, perfluoro-C₁-C₄ alkoxy, perfluoro-C₁-C₄alkoxy, (CH₂)₁₋₄OR′, (CH₂)₁₋₄NR′R″, (CH₂)₁₋₄SR′, (CH₂)₁₋₄SiR′R″R′″,(CH₂)₁₋₄OC(O)R′, (CH₂)₁₋₄C(O)R′, (CH₂)₁₋₄CO₂R′, (CH₂)₁₋₄CONR′R″, orcombinations thereof, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, unsubstituted aryl, and unsubstitutedheteroaryl. Other suitable substituents include each of the above arylsubstituents attached to a ring atom by an alkylene tether of from 1-4carbon atoms.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si). In some embodiments,heteroatom refers to O, N or S. In some embodiments, heteroatom refersto O or N.

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined. Unless otherwise specified, if solid wedges ordashed lines are used, relative stereochemistry is intended. If adiscrepancy exists between a structure and its name, the structuregoverns.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep.

A “subject,” “individual,” or “patient” is a vertebrate. In certainembodiments, the vertebrate is a mammal. A subject, individual orpatient may be in need of a compound of the present invention. In oneaspect, a subject, individual or patient is a human.

As used herein, the term “pharmaceutically acceptable salts” is meant toinclude salts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66,1-19). Certain specific compounds of the present invention contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,omithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyricacid, citrulline, homocysteine, homoserine, methyl-alanine,para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine,methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77: 285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing a radiolabeled(e.g., ¹⁴C or ³H) isotope of a compound of the invention, administeringit in a detectable dose (e.g., greater than about 0.5 mg/kg) to ananimal such as rat, mouse, guinea pig, monkey, or to man, allowingsufficient time for metabolism to occur (typically about 30 seconds to30 hours) and isolating its conversion products from the urine, blood orother biological samples. These products are easily isolated since theyare labeled (others are isolated by the use of antibodies capable ofbinding epitopes surviving in the metabolite). The metabolite structuresare determined in conventional fashion, e.g., by MS, LC/MS or NMRanalysis. In general, analysis of metabolites is done in the same way asconventional drug metabolism studies well known to those skilled in theart. The metabolite products, so long as they are not otherwise found invivo, are useful in diagnostic assays for therapeutic dosing of thecompounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. Compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are intended to be within the scope ofthe present invention.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, but for the fact that one or moreatoms are replace by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³ ₂P, ³³P,³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically labeled compounds ofthe present invention (e.g., those labeled with ³H or ¹⁴C) are useful incompound or substrate tissue distribution assays. Tritiated (³H) andcarbon-14 (¹⁴C) isotopes are useful for their ease of preparation anddetectability. Further substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent inventions can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and Examples herein, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

One non-limiting example of an isotopically substituted moiety is thefollowing:

The terms “compound(s) of this invention,” and “compound(s) of thepresent invention” and the like, unless otherwise indicated, includecompounds of formulae (I), (II) (A), (Aa), (Aa-1), (Aa-2), (B), (Ba),(Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) and (Da-2),and stereoisomers (including atropisomers), geometric isomers,tautomers, solvates, metabolites, isotopes, salts (e.g.,pharmaceutically acceptable salts), and prodrugs thereof. In someembodiments, solvates, metabolites, isotopes or prodrugs are excluded,or any combination thereof.

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include preventing occurrence or recurrence ofdisease, alleviation of symptoms, diminishment of any direct or indirectpathological consequences of the disease, stabilized (i.e., notworsening) state of disease, decreasing the rate of disease progression,amelioration or palliation of the disease state, prolonging survival ascompared to expected survival if not receiving treatment and remissionor improved prognosis. In some embodiments, compounds of the inventionare used to delay development of a disease or disorder or to slow theprogression of a disease or disorder. Those in need of treatment includethose already with the condition or disorder as well as those prone tohave the condition or disorder, (for example, through a geneticmutation) or those in which the condition or disorder is to beprevented. In some embodiments, prophylaxis is excluded from thedefinition of “treatment.”

The phrase “therapeutically effective amount” or “effective amount”means an amount of a compound of the present invention that (i) treatsor prevents the particular disease, condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, condition,or disorder described herein. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)or determining the response rate (RR). In the case of immunologicaldisease, the therapeutically effective amount is an amount sufficient todecrease or alleviate an allergic disorder, the symptoms of anautoimmune or inflammatory condition (e.g., psoriasis or inflammatorybowel disease), or the symptoms of an acute inflammatory reaction (e.g.,asthma). In some embodiments, a therapeutically effective amount is anamount of a chemical entity described herein sufficient to significantlydecrease the activity or number of B-cells.

The terms “inhibiting” and “reducing,” or any variation of these terms,includes any measurable decrease or complete inhibition to achieve adesired result. For example, there may be a decrease of about, at mostabout, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or anyrange derivable therein, reduction of activity (e.g., NIK activity)compared to normal.

The term “bioavailability” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

“Inflammatory condition” as used herein refers to any disease, disorder,or syndrome in which an excessive or unregulated inflammatory responseleads to excessive inflammatory symptoms, host tissue damage, or loss oftissue function.

“Inflammation” as used herein refers to a localized, protective responseelicited by injury or destruction of tissues, which serves to destroy,dilute, or wall off (sequester) both the injurious agent and the injuredtissue. Inflammation is notably associated with influx of leukocytes orneutrophil chemotaxis. Inflammation can result from infection withpathogenic organisms and viruses and from noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponse to foreign antigen, and autoimmune responses.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth or proliferation. A “tumor” comprises one ormore cancerous cells. Examples of cancer include, but are not limitedto, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents.

It is specifically contemplated that any limitation discussed withrespect to one embodiment of the invention may apply to any otherembodiment of the invention.

Furthermore, any compound or composition of the invention may be used inany method of the invention, and any method of the invention may be usedto produce or to utilize any compound or composition of the invention.

The use of the term “or” is used to mean “and/or” unless explicitlyindicated to refer to alternatives only or the alternative are mutuallyexclusive, although the disclosure supports a definition that refers toonly alternatives and “and/or.”

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value. In one aspect, “about” includesthe value per se. For example, about X includes and describes X per se.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Headings used herein are intended only for organizational purposes.

Inhibitors of NIK

One aspect of the invention provides a compound of formula (I):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:

ring A is a monocycle or a fused bicycle;

Q is N or C, wherein when Q is N, then the bond between A₁ and Q is nota double bond and the bond between Q and A₄ is not a double bond;

A₁ is NR¹, N, S, CR¹ or CHR¹;

A₂ is NR², N, O, S, CR² or CHR²;

A₃ is N or C;

A₄ is N; and

one, two or three of A₁-A₄ are N, wherein:

-   -   each R¹ is independently selected from the group consisting of        H, halogen, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), —NHS(O)₂—C₁-C₃        alkyl, C₁-C₃ alkyl, C₃-C₇ cycloalkyl, C₁-C₃ alkoxy and 3-11        membered heterocyclyl, wherein the C₁-C₃ alkyl of R¹ is        optionally substituted by F, OH, CN, SH, C₁-C₃ alkoxy or 3-11        membered heterocyclyl; the C₃-C₇ cycloalkyl of R¹ is optionally        substituted by F, OH, CN, SH, CH₃ or CF₃; the C₁-C₃ alkoxy of R¹        is optionally substituted by F, OH, CN or SH; and the 3-11        membered heterocyclyl of R¹ is optionally substituted by F, OH,        CN, SH, CF₃ or C₁-C₃ alkyl,    -   each R² is independently selected from the group consisting of        H, NR^(a)R^(b), C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy,        phenyl and 3-11 membered heterocyclyl, wherein the C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, phenyl and 3-11 membered        heterocyclyl of R² is optionally substituted by R^(c); or    -   R¹ and R² are taken together with the atoms to which they are        attached to form a cyclic group selected from the group        consisting of C₃-C₇ cycloalkyl, phenyl and 3-11 membered        heterocyclyl, wherein the cyclic group is optionally substituted        by R^(d);

each R^(4a) and R^(4b) is independently H or F;

R⁵ is C₁-C₆ alkyl or C₃-C₄ cycloalkyl, wherein the C₁-C₆ alkyl and C₃-C₄cycloalkyl of R⁵ are independently optionally substituted by halogen,OH, or C₁-C₆ alkoxy;

each A₅, A₆, A₇ and A₈ is independently N or CR⁶, provided that at leastthree of A₅, A₆, A₇ and A₈ are independently CR⁶;

each R⁶ is independently selected from the group consisting of H, F, Cl,NH₂, NHCH₃, N(CH₃)₂, OH, OCH₃, OCHF₂, OCH₂F, OCF₃, SH, SCH₃, SCHF₂,SCH₂F, CN, CH₃, CHF₂, CH₂F, CH₂OH, CF₃, NO₂ and N₃;

R^(a) is selected from the group consisting of H and C₁-C₆ alkyloptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃;

R^(b) is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₆ cycloalkyl, C(O)R^(g), phenyl and 3-11 memberedheterocyclyl wherein R^(b) may be optionally substituted by C₁-C₃alkoxy, F, OH, CN, SH, CH₃ or CF₃;

R^(c) and R^(d) are each independently selected from the groupconsisting of halogen, —(X¹)₀₋₁—CN, —(X¹)₀₋₁—NO₂, —(X¹)₀₋₁—SF₅,—(X¹)₀₋₁—OH, —(X¹)₀₋₁—NH₂, —(X¹)₀₋₁N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))(R^(1a)), —(X¹)₀₋₁—CF₃, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, oxo, —(X¹)₀₋₁—C₁-C₆alkyl, —(X¹)₀₋₁—C₃-C₁₀ cycloalkyl, —O—C₃-C₁₀ cycloalkyl, —(X¹)₀₋₁-3-11membered heterocyclyl, —(X¹)₀₋₁—C₆-C₁₀ aryl, —C(═O)(X¹)₀₋₁—C₃-C₁₀cycloalkyl, —C(═O)(X¹)₀₋₁-3-11 membered heterocyclyl,—(X¹)₀₋₁—C(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—C(═Y¹)NH₂,—(X¹)₀₋₁—C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—C(═Y¹)OR^(1a),—(X¹)₀₋₁—C(═Y¹)OH, —(X¹)₀₋₁—N(H)C(═Y¹)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))C(═Y¹)(R^(1a)), —(X¹)₀₋₁—N(R^(1b))C(═Y¹)(H),—(X¹)₀₋₁—N(H)C(═Y¹)(R^(1a)), N(R^(1b))C(═Y¹)OR^(1a),—(X¹)₀₋₁—S(O)₁₋₂R^(1a), —(X¹)₀₋₁—N(H)S(O)₁₋₂R^(1a),—(X¹)₀₋₁—N(R^(1b))S(O)₁₋₂R^(1a), —(X¹)₀₋₁—S(O)₀₋₁N(H)(R^(1a)),—(X¹)₀₋₁—S(O)₀₋₁N(R^(1b))(R^(1a)), —(X¹)₀₋₁—S(O)₀₋₁NH₂,—(X¹)₀₋₁—S(═O)(═NR^(1b))R^(1a), —(X¹)₀₋₁—C(═Y¹)R^(1a), —(X¹)₀₋₁—C(═Y¹)H,—(X¹)₀₋₁—C(═NOH)R^(1a), —(X¹)₀₋₁—C(═NOR^(1b))R^(1a),—(X¹)₀₋₁—NHC(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—NHC(═Y¹)NH₂,—(X¹)₀₋₁—NHC(═Y¹)N(R^(1b))(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—N(R^(1a))C(═Y¹)NH₂,—(X¹)₀₋₁—OC(═Y¹)R^(1a), —(X¹)₀₋₁—OC(═Y¹)H, —(X¹)₀₋₁—OC(═Y¹)OR^(1a),—(X¹)₀₋₁—OP(═Y¹)(OR^(1a))(OR^(1b)), —(X¹)—SC(═Y¹)OR^(1a) and—(X¹)—SC(═Y¹)N(R^(1a))(R^(1b)); wherein X¹ is selected from the groupconsisting of C₁-C₆ alkylene, C₁-C₆ heteroalkylene, C₂-C₆ alkenylene,C₂-C₆ alkynylene, C₁-C₆ alkyleneoxy, C₃-C₇ cycloalkylene, 3-11 memberedheterocyclylene and phenylene; R^(1a) and R^(1b) are each independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkylene)C₁-C₆ alkyl,3-11 membered heterocyclyl, (3-11 membered heterocyclylene)C₁-C₆ alkyl,phenyl, and (C₆-C₁₀ arylene)C₁-C₆ alkyl, or R^(1a) and R^(1b), whenattached to the same nitrogen atom, are taken together with the nitrogento which they are attached to form a 3-11 membered heterocyclylcomprising 0-3 additional heteroatoms selected from N, O and S; Y¹ is O,NR^(1c) or S wherein R^(1c) is H or C₁-C₆ alkyl; wherein any portion ofan R^(c) or R^(d) substituent, including R^(1a), R^(1b) and R^(1c), ateach occurrence is independently further substituted by from 0 to 4R^(f) substituents selected from the group consisting of halogen, CN,NO₂, SF₅, OH, NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), oxo, C₁-C₆ alkyl,—(C₂-C₆ alkynylene)-(3-11 membered heterocyclyl, wherein theheterocyclyl is optionally substituted by R^(e)), C₁-C₆ hydroxyalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl, 3-11membered heterocyclyl, —C(═O)N(H)(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—C(═O)NH₂, —C(═O)OC₁-C₆ alkyl, —C(═O)OH, —N(H)C(═O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(═O)(C₁-C₆ alkyl), —N(H)C(═O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(═O)OC₁-C₆ (halo)alkyl, —S(O)₁₋₂C₁-C₆ alkyl, —N(H)S(O)₁₋₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₁₋₂C₁-C₆ alkyl, —S(O)₀₋₁N(H)(C₁-C₆ alkyl),—S(O)₀₋₁N(C₁-C₆ alkyl)₂, —S(O)₀₋₁NH₂, —C(═O)C₁-C₆ alkyl, —C(═O)C₃-C₇cycloalkyl, —C(═NOH)C₁-C₆ alkyl, —C(═NOC₁-C₆ alkyl)C₁-C₆ alkyl,—NHC(═O)N(H)(C₁-C₆ alkyl), —NHC(═O)N(C₁-C₆ alkyl)₂, —NHC(═O)NH₂,—N(C₁-C₆ alkyl)C(═O)N(H)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(═O)NH₂,—OC(═O)C₁-C₆ alkyl, —OC(═O)OC₁-C₆ alkyl, —OP(═O)(OC₁-C₆ alkyl)₂,—SC(═O)OC₁-C₆ alkyl and —SC(═O)N(C₁-C₆ alkyl)₂, wherein any alkylportion of R^(f) is optionally substituted with halogen;

R^(e) is selected from the group consisting of halogen, OH, C₁-C₆ alkyland oxo; and

R^(g) is selected from the group consisting of C₁-C₆ alkyl and C₃-C₆cycloalkyl wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl of R^(g) may beoptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃.

In some embodiments, the compound is of the formula (I), provided thatno more than two of (i)-(iii) apply: (i) A₁ is NR¹ or N, (ii) A₂ is NR²or N, and (iii) A₃ is N. In some embodiments, the compound is of theformula (I), provided at least one of (iv)-(vi) applies: (iv) A₁ is S,CR¹ or CHR¹; (v) A₂ is O, S, CR² or CHR²; and (vi) A₃ is C.

In some embodiments, ring A is an unsaturated monocycle or anunsaturated fused bicycle.

In some embodiments, a compound of formula (I) is further defined as acompound of formula (II):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:

ring A is a monocycle or a fused bicycle;

A₁ is NR¹, N, S, CR¹ or CHR¹;

A₂ is NR², N, O, S, CR² or CHR²;

A₃ is N or C;

each R¹ is independently selected from the group consisting of H,halogen, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), —NHS(O)₂—C₁-C₃ alkyl, C₁-C₃alkyl, C₃-C₇ cycloalkyl, C₁-C₃ alkoxy and 3-11 membered heterocyclyl,wherein the C₁-C₃ alkyl of R¹ is optionally substituted by F, OH, CN,SH, C₁-C₃ alkoxy or 3-11 membered heterocyclyl; the C₃-C₇ cycloalkyl ofR¹ is optionally substituted by F, OH, CN, SH, CH₃ or CF₃; the C₁-C₃alkoxy of R¹ is optionally substituted by F, OH, CN or SH; and the 3-11membered heterocyclyl of R¹ is optionally substituted by F, OH, CN, SH,CF₃ or C₁-C₃ alkyl,

each R² is independently selected from the group consisting of H,NR^(a)R^(b), C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, phenyl and3-11 membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₁-C₆ alkoxy, phenyl and 3-11 membered heterocyclyl of R² is optionallysubstituted by R^(c); or

-   -   R¹ and R² are taken together with the atoms to which they are        attached to form a cyclic group selected from the group        consisting of C₃-C₇ cycloalkyl, phenyl and 3-11 membered        heterocyclyl, wherein the cyclic group is optionally substituted        by R^(d);

each R^(4a) and R^(4b) is independently H or F;

R⁵ is C₁-C₆ alkyl or C₃-C₄ cycloalkyl, wherein the C₁-C₆ alkyl and C₃-C₄cycloalkyl of R⁵ are independently optionally substituted by halogen,OH, or C₁-C₆ alkoxy;

each A₅, A₆, A₇ and A₈ is independently N or CR⁶, provided that at leastthree of A₅, A₆, A₇ and A₈ are independently CR⁶;

each R⁶ is independently selected from the group consisting of H, F, Cl,NH₂, NHCH₃, N(CH₃)₂, OH, OCH₃, OCHF₂, OCH₂F, OCF₃, SH, SCH₃, SCHF₂,SCH₂F, CN, CH₃, CHF₂, CH₂F, CH₂OH, CF₃, NO₂ and N₃;

R^(a) is selected from the group consisting of H and C₁-C₆ alkyloptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃;

R^(b) is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₆ cycloalkyl, C(O)R^(g), phenyl and 3-11 memberedheterocyclyl wherein R^(b) may be optionally substituted by C₁-C₃alkoxy, F, OH, CN, SH, CH₃ or CF₃;

R^(c) and R^(d) are each independently selected from the groupconsisting of halogen, —(X¹)₀₋₁—CN, —(X¹)₀₋₁—NO₂, —(X¹)₀₋₁—SF₅,—(X¹)₀₋₁—OH, —(X¹)₀₋₁—NH₂, —(X¹)₀₋₁—N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))(R^(1a)), —(X¹)₀₋₁—CF₃, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, oxo, —(X¹)₀₋₁—C₁-C₆alkyl, —(X¹)₀₋₁—C₃-C₁₀ cycloalkyl, —O—C₃-C₁₀ cycloalkyl, —(X¹)₀₋₁-3-11membered heterocyclyl, —(X¹)₀₋₁—C₆-C₁₀ aryl, —C(═O)(X¹)₀₋₁—C₃-C₁₀cycloalkyl, —C(═O)(X¹)₀₋₁-3-11 membered heterocyclyl,—(X¹)₀₋₁—C(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—C(═Y¹)NH₂,—(X¹)₀₋₁—C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—C(═Y¹)OR^(1a),—(X¹)₀₋₁—C(═Y¹)OH, —(X¹)₀₋₁—N(H)C(═Y¹)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))(═Y¹)(R^(1a)), —(X¹)₀₋₁—N(R^(1b))C(═Y)(H),—(X¹)₀₋₁—N(H)C(═Y¹)OR^(1a), —(X¹)₀₋₁—N(R^(1b))C(═Y¹)OR^(1a),—(X¹)₀₋₁—S(O)₁₋₂R^(1a), —(X¹)₀₋₁—N(H)S(O)₁₋₂R^(1a),—(X¹)₀₋₁—N(R^(1b))S(O)₁₋₂R^(1a), —(X¹)₀₋₁—S(O)₀₋₁N(H)(R^(1a)),—(X¹)₀₋₁—S(O)₀₋₁N(R^(1b))(R^(1a)), —(X¹)₀₋₁—S(O)₀₋₁NH₂,—(X¹)₀₋₁—S(═O)(═NR^(1b))R^(1a), —(X¹)₀₋₁—C(═Y¹)R^(1a), —(X¹)₀₋₁—C(═Y¹)H,—(X¹)₀₋₁—C(═NOH)R^(1a), —(X¹)₀₋₁—C(═NOR^(1b))R^(1a),—(X¹)₀₋₁—NHC(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—NHC(═Y¹)NH₂,—(X¹)₀₋₁—NHC(═Y)N(R^(1b))(R^(1a)), —(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—N(R^(1a))C(═Y¹)NH₂,—(X¹)₀₋₁—OC(═Y¹)R^(1a), —(X¹)₀₋₁—OC(═Y¹)H, —(X¹)₀₋₁—OC(═Y¹)OR^(1a),—(X¹)₀₋₁—OP(═Y¹)(OR^(1a))(OR^(1b)), —(X¹)—SC(═Y¹)OR¹a and—(X¹)—SC(═Y¹)N(R^(1a))(R^(1b)); wherein X¹ is selected from the groupconsisting of C₁-C₆ alkylene, C₁-C₆ heteroalkylene, C₂-C₆ alkenylene,C₂-C₆ alkynylene, C₁-C₆ alkyleneoxy, C₃-C₇ cycloalkylene, 3-11 memberedheterocyclylene and phleylene; R^(1a) and R^(1b) are each independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkylene)C₁-C₆ alkyl,3-11 membered heterocyclyl, (3-11 membered heterocyclylene)C₁-C₆ alkyl,phenyl, and (C₆-C₁₀ arylene)C₁-C₆ alkyl, or R^(1a) and R^(1b), whenattached to the same nitrogen atom, are taken together with the nitrogento which they are attached to form a 3-11 membered heterocyclylcomprising 0-3 additional heteroatoms selected from N, O and S; Y¹ is O,NR^(1c) or S wherein R^(1c) is H or C₁-C₆ alkyl; wherein any portion ofan R^(c) or R^(d) substituent, including R^(1a), R^(1b) and R^(1c), ateach occurrence is independently further substituted by from 0 to 4R^(f) substituents selected from the group consisting of halogen, CN,NO₂, SF₅, OH, NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), oxo, C₁-C₆ alkyl,—(C₂-C₆ alkynylene)-(3-11 membered heterocyclyl, wherein theheterocyclyl is optionally substituted by R^(e)), C₁-C₆ hydroxyalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl, 3-11membered heterocyclyl, —C(═O)N(H)(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—C(═O)NH₂, —C(═O)OC₁-C₆ alkyl, —C(═O)OH, —N(H)C(═O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(═O)(C₁-C₆ alkyl), —N(H)C(═O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(═O)OC₁-C₆ (halo)alkyl, —S(O)₁₋₂C₁-C₆ alkyl, —N(H)S(O)₁₋₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₁₋₂C₁-C₆ alkyl, —S(O)₀₋₁N(H)(C₁-C₆ alkyl),—S(O)₀₋₁N(C₁-C₆ alkyl)₂, —S(O)₀₋₁NH₂, —C(═O)C₁-C₆ alkyl, —C(═O)C₃-C₇cycloalkyl, —C(═NOH)C₁-C₆ alkyl, —C(═NOC₁-C₆ alkyl)C₁-C₆ alkyl,—NHC(═O)N(H)(C₁-C₆ alkyl), —NHC(═O)N(C₁-C₆ alkyl)₂, —NHC(═O)NH₂,—N(C₁-C₆ alkyl)C(═O)N(H)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(═O)NH₂,—OC(═O)C₁-C₆ alkyl, —OC(═O)OC₁₋C₆ alkyl, —OP(═O)(OC₁-C₆ alkyl)₂,—SC(═O)OC₁-C₆ alkyl and —SC(═O)N(C₁-C₆ alkyl)₂, wherein any alkylportion of R′ is optionally substituted with halogen;

R^(e) is selected from the group consisting of halogen, OH, C₁-C₆ alkyland oxo; and

R^(g) is selected from the group consisting of C₁-C₆ alkyl and C₃-C₆cycloalkyl wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl of R^(g) may beoptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃.

In some embodiments, the compound is of the formula (II), provided thatno more than two of (i)-(iii) apply: (i) A₁ is NR¹ or N, (ii) A₂ is NR²or N, and (iii) A₃ is N. In some embodiments, the compound is of theformula (II), provided at least one of (iv)-(vi) applies: (iv) A₁ is S,CR¹ or CHR¹; (v) A₂ is O, S, CR² or CHR²; and (vi) A₃ is C.

In some embodiments, ring A is an unsaturated monocycle or anunsaturated fused bicycle.

In some embodiments of the compounds of formula (I) or (II), ring A is amonocycle.

In some embodiments, ring A is a monocyclic heteroaryl containing one ortwo ring nitrogen atoms (e.g., a thiazole or imidazole). In someembodiments, A₁ is N or CHR¹. In some embodiments, A₁ is N. In someembodiments, A₁ is N, A₂ is S and A₃ is C (ring A is a thiadiazole). Insome embodiments, A₂ is N, O or CHR². In some embodiments, A₂ is N. Insome embodiments, A₁ is S, A₂ is N and A₃ is C (ring A is athiadiazole). In some embodiments, A₁ is CR¹, A₂ is O and A₃ is C (ringA is an oxazole). In some embodiments, A₁ is CR¹, A₂ is S and A₃ is C(ring A is a thiazole). In some embodiments, A₁ is CR¹, A₂ is NR² and A₃is C (ring A is an imidazole).

In some embodiments of the compounds of formula (I) or (II), A₁ is CHR¹and A₂ is CHR², and ring A is a non-aromatic heterocycle. In someembodiments, A₁ is CHR¹ and A₂ is CHR², and ring A is a non-aromaticmonocyclic heterocycle. In some embodiments, A₁ is CHR¹ and A₂ is CHR²,and ring A is a fused bicyclic non-aromatic heterocycle. In someembodiments, A₁ is CHR¹; A₂ is CHR²; and R¹ and R² are taken togetherwith the atoms to which they are attached to form a C₃-C₇ cycloalkyloptionally substituted by R^(d) or a 3-11 membered heterocyclyloptionally substituted by R^(d). In some embodiments, R¹ and R² togetherform the following cyclic group, wherein the asterisks indicate thepoints of ring fusion to ring A, and each cyclic group is optionallysubstituted by R^(d):

In some embodiments of the compounds of formula (I) or (II), A₁ is NR¹,S or CR¹; and A₂ is NR², S or CR². In some embodiments, A₁ is S. In someembodiments, A₁ is S, A₂ is CR² and A₃ is C. In some embodiments, R² isH.

In some embodiments of the compounds of formula (I) or (II), A₇ is CR⁶where R⁶ is H. In some embodiments, A₈ is CR⁶ where R⁶ is H or F. Insome embodiments, A₅ is CR⁶ where R⁶ is H. In some embodiments, A₆ isCR⁶ where R⁶ is selected from the group consisting of H, F, OCH₃ andCH₃. In some embodiments, ring B is phenyl (i.e., each A₅-A₈ isindependently CR⁶). In some embodiments, each A₅-A₈ is CH.

In some embodiments of the compounds of formula (I) or (II), each R^(4a)and R^(4b) is independently H or F; and R⁵ is C₁-C₆ alkyl optionallysubstituted by halogen, OH, or C₁-C₆ alkoxy or C₃-C₄ cycloalkyloptionally substituted by halogen, OH, or C₁-C₆ alkoxy. In someembodiments, each R^(4a) and R^(4b) is H. In some embodiments, eachR^(4a) and R^(4b) is F. In some embodiments, R⁵ is C₁-C₆ alkyloptionally substituted by halogen, OH, or C₁-C₆ alkoxy. In someembodiments, R⁵ is C₃-C₄ cycloalkyl optionally substituted by halogen,OH, or C₁-C₆ alkoxy. In some embodiments, R⁵ is C₁-C₆ alkyl. In someembodiments, R⁵ is C₁-C₃ alkyl (e.g., methyl).

It is intended and understood that each and every variation of A₁-A₄,including variations of R¹ and R² where applicable, described forformula (I) or (II) may be combined with each and every variation ofA₅-A₈ described for formula (I) or (II), and with each and everyvariation of R^(4a), R^(4b) and R⁵ described for Formula (I) or (II) orany variation described herein as if each and every combination isindividually described. For example, in some embodiments of thecompounds of formula (I) or (II), or a stereoisomer, tautomer, solvate,prodrug or salt thereof, ring A is a thiazole (e.g., A₁ is CR¹, A₂ is S,A₃ is C and A₄ is N); ring B is phenyl (e.g., each A₅-A₈ is CH); eachR^(4a) and R^(4b) is H; and R⁵ is methyl.

In some embodiments, a compound of formula (I) is further defined as acompound of formula (A):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:

ring A is a monocycle or a fused bicycle;

A₁ is NR¹ or CR¹;

A₂ is NR², S or CR²;

A₃ is N or C;

each R¹ is independently selected from the group consisting of H,halogen, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), —NHS(O)₂—C₁-C₃ alkyl, C₁-C₃alkyl, C₃-C₇ cycloalkyl, C₁-C₃ alkoxy and 3-11 membered heterocyclyl,wherein the C₁-C₃ alkyl of R¹ is optionally substituted by F, OH, CN,SH, C₁-C₃ alkoxy or 3-11 membered heterocyclyl; the C₃-C₇ cycloalkyl ofR¹ is optionally substituted by F, OH, CN, SH, CH₃ or CF₃; the C₁-C₃alkoxy of R¹ is optionally substituted by F, OH, CN or SH; and the 3-11membered heterocyclyl of R¹ is optionally substituted by F, OH, CN, SH,CF₃ or C₁-C₃ alkyl,

each R² is independently selected from the group consisting of H,NR^(a)R^(b), C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, phenyl and3-11 membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₁-C₆ alkoxy, phenyl and 3-11 membered heterocyclyl of R² is optionallysubstituted by R^(c); or

-   -   R¹ and R² are taken together with the atoms to which they are        attached to form a cyclic group selected from the group        consisting of C₃-C₇ cycloalkyl, phenyl and 3-11 membered        heterocyclyl, wherein the cyclic group is optionally substituted        by R^(d);

each R^(4a) and R^(4b) is independently H or F;

R⁵ is C₁-C₆ alkyl or C₃-C₄ cycloalkyl, wherein the C₁-C₆ alkyl and C₃-C₄cycloalkyl of R⁵ are independently optionally substituted by halogen,OH, or C₁-C₆ alkoxy;

n is 0, 1, 2, 3 or 4;

each R⁶ is independently selected from the group consisting of H, F, Cl,NH₂, NHCH₃, N(CH₃)₂, OH, OCH₃, OCHF₂, OCH₂F, OCF₃, SH, SCH₃, SCHF₂,SCH₂F, CN, CH₃, CHF₂, CH₂F, CH₂OH, CF₃, NO₂ and N₃;

R^(a) is selected from the group consisting of H and C₁-C₆ alkyloptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃;

R^(b) is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₆ cycloalkyl, C(O)R^(g), phenyl and 3-11 memberedheterocyclyl wherein R^(b) may be optionally substituted by C₁-C₃alkoxy, F, OH, CN, SH, CH₃ or CF₃;

R^(c) and R^(d) are each independently selected from the groupconsisting of halogen, —(X¹)₀₋₁—CN, —(X¹)₀₋₁—NO₂, —(X¹)₀₋₁—SF₅,—(X¹)₀₋₁—OH, —(X¹)₀₋₁—NH₂, —(X¹)₀₋₁—N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))(R^(1a)), —(X¹)₀₋₁—CF₃, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, oxo, —(X¹)₀₋₁—C₁-C₆alkyl, —(X¹)₀₋₁—C₃-C₁₀ cycloalkyl, —O—C₃-C₁₀ cycloalkyl, —(X¹)₀₋₁-3-11membered heterocyclyl, —(X¹)₀₋₁—C₆-C₁₀ aryl, —C(═O)(X¹)₀₋₁—C₃-C₁₀cycloalkyl, —C(═O)(X¹)₀₋₁-3-11 membered heterocyclyl,—(X¹)₀₋₁—C(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—C(═Y¹)NH₂,—(X¹)₀₋₁—C(═Y¹)N(R^(1a))(R^(1b)), (X¹)₀₋₁—C(═Y¹)OR^(1a),—(X¹)₀₋₁—C(═Y¹)OH, —(X¹)₀₋₁—N(H)C(═Y¹)(R^(1a)),—(X¹)₀₋₁—N(R^(b))C(═Y¹)(R^(1a)), —(X¹)₀₋₁—N(R^(1b))₀₋₁—C(═Y)(H),—(X¹)₀₋₁—N(H)C(═Y¹)OR^(1a), —(X¹)₀₋₁—N(R^(1b))C(═Y¹)OR^(1a),—(X¹)₀₋₁—S(O)₁₋₂R^(1a), —(X¹)₀₋₁—N(H)S(O)₁₋₂R^(1a),—(X¹)₀₋₁—N(R^(1b))S(O)₁₋₂R^(1a), —(X¹)₀₋₁—S(O)₀₋₁N(H)(R^(1a)),—(X¹)₀₋₁—S(O)₀₋₁N(R^(1b))(R^(1a)), —(X¹)₀₋₁—S(O)₀₋₁NH₂,—(X¹)₀₋₁—S(═O)(═NR^(1b))R^(1a), —(X¹)₀₋₁—C(═Y¹)R^(1a), —(X¹)₀₋₁—C(═Y¹)H,—(X¹)₀₋₁—C(═NOH)R^(1a), —(X¹)₀₋₁—C(═NOR^(1b))R^(1a),—(X¹)₀₋₁—NHC(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—NHC(═Y¹)NH₂,—(X¹)₀₋₁—NHC(═Y¹)N(R^(1b))(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—N(R^(1a))C(═Y¹)NH₂,—(X¹)₀₋₁—OC(═Y¹)R^(1a), —(X¹)₀₋₁—OC(═Y¹)H, —(X¹)₀₋₁—OC(═Y)OR^(1a),—(X¹)₀₋₁—OP(═Y¹)(OR^(1a))(OR^(1b)), —(X¹)—SC(═Y¹)OR^(1a) and—(X¹)—SC(═Y¹)N(R^(1a))(R^(1b)); wherein X¹ is selected from the groupconsisting of C₁-C₆ alkylene, C₁-C₆ heteroalkylene, C₂-C₆ alkenylene,C₂-C₆ alkynylene, C₁-C₆ alkyleneoxy, C₃-C₇ cycloalkylene, 3-11 memberedheterocyclylene and phenylene; R^(1a) and R^(1b) are each independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkylene)C₁-C₆ alkyl,3-11 membered heterocyclyl, (3-11 membered heterocyclylene)C₁-C₆ alkyl,phenyl, and (C₆-C₁₀ arylene)C₁-C₆ alkyl, or R^(1a) and R^(1b), whenattached to the same nitrogen atom, are taken together with the nitrogento which they are attached to form a 3-11 membered heterocyclylcomprising 0-3 additional heteroatoms selected from N, O and S; Y¹ is O,NR^(1c) or S wherein R^(1c) is H or C₁-C₆ alkyl; wherein any portion ofan R^(c) or R^(d) substituent, including R^(1a), R^(1b) and R^(1c), ateach occurrence is independently further substituted by from 0 to 4R^(f) substituents selected from the group consisting of halogen, CN,NO₂, SF₅, OH, NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), oxo, C₁-C₆ alkyl,—(C₂-C₆ alkynylene)-(3-11 membered heterocyclyl, wherein theheterocyclyl is optionally substituted by R^(e)), C₁-C₆ hydroxyalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl, 3-11membered heterocyclyl, —C(═O)N(H)(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—C(═O)NH₂, —C(═O)OC₁-C₆ alkyl, —C(═O)OH, —N(H)C(═O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(═O)(C₁-C₆ alkyl), —N(H)C(═O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(═O)OC₁-C₆ (halo)alkyl, —S(O)₁₋₂C₁-C₆ alkyl, —N(H)S(O)₁₋₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₁₋₂C₁-C₆ alkyl, —S(O)₀₋₁N(H)(C₁-C₆ alkyl),—S(O)₀₋₁N(C₁-C₆ alkyl)₂, —S(O)₀₋₁NH₂, —C(═O)C₁-C₆ alkyl, —C(═O)C₃-C₇cycloalkyl, —C(═NOH)C₁-C₆ alkyl, —C(═NOC₁-C₆ alkyl)C₁-C₆ alkyl,—NHC(═O)N(H)(C₁-C₆ alkyl), —NHC(═O)N(C₁-C₆ alkyl)₂, —NHC(═O)NH₂,—N(C₁-C₆ alkyl)C(═O)N(H)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(═O)NH₂,—OC(═O)C₁-C₆ alkyl, —OC(═O)OC₁-C₆ alkyl, —OP(═O)(OC₁-C₆ alkyl)₂,—SC(═O)OC₁-C₆ alkyl and —SC(═O)N(C₁-C₆ alkyl)₂, wherein any alkylportion of R^(f) is optionally substituted with halogen;

R^(e) is selected from the group consisting of halogen, OH, C₁-C₆ alkyland oxo; and

R^(g) is selected from the group consisting of C₁-C₆ alkyl and C₃-C₆cycloalkyl wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl of R^(g) may beoptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃.

In some embodiments, the compound is of the formula (A), provided thatno more than two of (i)-(iii) apply: (i) A₁ is NR¹; (ii) A₂ is NR²; and(iii) A₃ is N. In some embodiments, the compound is of the formula (A),provided at least one of (iv)-(vi) apply: (iv) A₁ is CR¹; (v) A₂ is S orCR²; and (vi) A₃ is C.

In some embodiments, ring A is an unsaturated monocycle or anunsaturated fused bicycle.

In some embodiments, a compound of formula (A) is further defined as acompound of formula (Aa):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R^(4a), R^(4b), R⁵, R⁶ and n are as defined for formula (A),or any variation thereof.

In some embodiments, a compound of formula (A) is further defined as acompound of formula (Aa-1):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R^(4a), R^(4b), R⁵, R⁶ and n are as defined for formula (A),or any variation thereof.

In some embodiments, a compound of formula (A) is further defined as acompound of formula (Aa-2):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R^(4a), R^(4b), R⁵, R⁶ and n are as defined for formula (A),or any variation thereof.

In some embodiments, a compound of formula (A), wherein n is 0, isfurther defined as a compound of formula (B):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R^(4a), R^(4b) and R⁵ are as defined for formula (A), or anyvariation thereof.

In some embodiments, a compound of formula (B) is further defined as acompound of formula (Ba):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R^(4a), R^(4b) and R⁵ are as defined for formula (B), or anyvariation thereof.

In some embodiments, a compound of formula (B) is further defined as acompound of formula (Ba-1):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R^(4a), R^(4b) and R⁵ are as defined for formula (B), or anyvariation thereof.

In some embodiments, a compound of formula (B) is further defined as acompound of formula (Ba-2):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R^(4a), R^(4b) and R⁵ are as defined for formula (B), or anyvariation thereof.

One aspect of the invention provides a compound of formula (C):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:

ring A is a monocycle or a fused bicycle;

A₁ is NR¹ or CR¹;

A₂ is NR², S or CR²;

A₃ is N or C;

provided that no more than one of (i)-(iii) applies: (i) A₁ is NR¹, (ii)A₂ is NR², and (iii) A₃ is N;

each R¹ is independently —NR^(a)R^(b); C₁-C₃ alkyl optionallysubstituted by F, OH, CN, SH or C₁-C₃ alkoxy; or taken together with R²,where present, and the atoms to which they are attached to form a6-membered heterocyclyl optionally substituted by R^(d);

each R² is independently absent or taken together with R¹ and the atomsto which they are attached to form a 6-membered heterocyclyl optionallysubstituted by R^(d);

n is 0 or 1;

R⁶, where present, is halo;

each R^(a) and R^(b) is independently selected from the group consistingof H and C₁-C₆ alkyl; and

each R^(d) is independently selected from the group consisting of C₁-C₆alkyl optionally substituted by halogen and C₁-C₆ alkoxy optionallysubstituted by halogen.

It is understood that in the compound of the formula (C), no more thanone of (i)-(iii) applies: (i) A₁ is NR¹; (ii) A₂ is NR²; and (iii) A₃ isN. It is also understood that in the compound is of the formula (C), atleast two of (iv)-(vi) apply: (iv) A₁ is CR¹; (v) A₂ is S or CR²; and(vi) A₃ is C.

In some embodiments, ring A is an unsaturated monocycle or anunsaturated fused bicycle.

In some embodiments, a compound of formula (C) is further defined as acompound of formula (Ca):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R⁶ and n are as defined for formula (C), or any variationthereof.

In some embodiments, a compound of formula (C) is further defined as acompound of formula (Ca-1):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R⁶ and n are as defined for formula (C), or any variationthereof.

In some embodiments, a compound of formula (C) is further defined as acompound of formula (Ca-2):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂, A₃, R⁶ and n are as defined for formula (C), or any variationthereof.

In some embodiments, a compound of formula (C), wherein n is 0, isfurther defined as a compound of formula (D):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂ and A₃ are as defined for formula (C), or any variation thereof.

In some embodiments, a compound of formula (D) is further defined as acompound of formula (Da):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA, A₂ and A₃ are as defined for formula (D), or any variation thereof.

In some embodiments, a compound of formula (D) is further defined as acompound of formula (Da-1):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂ and A₃ are as defined for formula (D), or any variation thereof.

In some embodiments, a compound of formula (D) is further defined as acompound of formula (Da-2):

or a stereoisomer, tautomer, solvate, prodrug or salt thereof, whereinA₁, A₂ and A₃ are as defined for formula (D), or any variation thereof.

In some embodiments of the compound of formula (I), (II) (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1) or (Da-2), or any applicable variations thereof, or astereoisomer, tautomer, solvate, prodrug or salt thereof, ring A is amonocycle. In some embodiments, A₁ is NR¹. In some embodiments, A₁ isCR¹. In some of these embodiments, R¹ is NH₂. In some embodiments, A₂ isNR². In some embodiments, A₂ is S. In some embodiments, A₃ is C. In someembodiments, A₁ is CR¹, A₂ is S, and A₃ is C. In some embodiments, A₁ isCR¹ where R¹ is NH₂, A₂ is S, and A₃ is C. In some embodiments, A isCR¹, A₂ is NR², and A₃ is C.

In some embodiments of the compound of formula (I), (II) (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1) or (Da-2), or any applicable variations thereof, or astereoisomer, tautomer, solvate, prodrug or salt thereof), A₁ is CR¹wherein R¹ is selected from the group consisting of NHC(O)NR^(a)R^(b);NHS(O)₂CH₃; C₁-C₃ alkyl substituted by C₁-C₃ alkoxy or 3-11 memberedheterocyclyl; and 3-11 membered heterocyclyl substituted by C₁-C₃ alkyl.In some embodiments, A₁ is CR¹ wherein R¹ is NHC(O)NR^(a)R^(b). In someof these embodiments, R^(a) and R^(b) are independently selected fromthe group consisting of H and C₁-C₆ alkyl. In some embodiments, A₁ isCR¹ wherein R¹ is NHS(O)₂CH₃. In some embodiments, A₁ is CR¹ wherein R¹is 3-11 membered heterocyclyl substituted by C₁-C₃ alkyl. In someembodiments, A, is CR¹ wherein R¹ is C₁-C₃ alkyl substituted by C₁-C₃alkoxy or 3-11 membered heterocyclyl.

In some embodiments, R¹ is selected from the group consisting of H, Fand C₁.

In some embodiments, R¹ is NR^(a)R^(b). In some of these embodiments,R^(a) is H or C₁-C₆ alkyl. In some of these embodiments, R^(b) is H;C₁-C₆ alkyl optionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃or CF₃; or 3-11 membered heterocyclyl optionally substituted by C₁-C₃alkoxy, F, OH, CN, SH, CH₃ or CF₃. In some of these embodiments, R^(b)is C(O)R^(g). In some embodiments, R^(g) is C₃-C₆ cycloalkyl optionallysubstituted by F. In some embodiments, R¹ is NH₂.

In some embodiments, A₁ is NR¹. In some embodiments, A, is NR¹, A₂ isCR² and A₃ is C. In some of these embodiments, R¹ is H or C₁-C₃ alkyl.In some of these embodiments, R¹ is C₁-C₃ alkyl. In some embodiments, A₁is CR¹. In some embodiments, A₁ is CR¹, A₂ is CR² and A₃ is N. In someembodiments, A₁ is CR¹ and A₆ is CR⁶. In some of these embodiments, A₂is CR² where R² is H or —OCH₃.

In some embodiments, R¹ is C₁-C₃ alkyl optionally substituted by F, OH,CN, SH, C₁-C₃ alkoxy or 3-11 membered heterocyclyl; C₃-C₇ cycloalkyloptionally substituted by F, OH, CN, SH, CH₃ or CF₃; or C₁-C₃ alkoxy. Insome embodiments, R¹ is C₁-C₃ alkyl optionally substituted by F, OH, CN,SH or C₁-C₃ alkoxy.

In some embodiments, R¹ is 3-11 membered heterocyclyl optionallysubstituted by F, OH, CN, SH, CF₃ or C₁-C₃ alkyl.

In some embodiments, R¹ is a 5-6 membered heteroaryl optionallysubstituted by F, OH, CN, SH, CF₃ or C₁-C₃ alkyl.

In some embodiments, R¹ is selected from the group consisting of:

wherein the wavy line represents the point of attachment of R¹ in theparent structure.

In some embodiments, R² is selected from the group consisting of H, NH₂,CH₃ and cyclopropyl. In other embodiments, R² is a C₃-C₁₁heterocycloalkyl.

In some embodiments, A₁ is NR¹ or CR¹; and A₂ is NR² or CR².

In some embodiments of the compound of formula (I), (II) (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1) or (Da-2), or any applicable variations thereof, or astereoisomer, tautomer, solvate, prodrug or salt thereof, ring A is afused bicycle. In some embodiments, A₁ is NR¹ or CR¹, A₂ is NR² or CR²,and R¹ and R² are taken together with the atoms to which they areattached to form a 3-11 membered heterocyclyl optionally substituted byR^(d). In some of these embodiments, A₁ is CR¹, A₂ is CR² and A₃ is N.In some of these embodiments, A₁ is NR¹, A₂ is CR² and A₃ is C. In someof these embodiments, A₁ is CR¹, A₂ is NR² and A₃ is C.

In some embodiments, R¹ and R² together form the following cyclic group,wherein the asterisks indicate the points of ring fusion to ring A, andeach cyclic group is optionally substituted by R^(d):

In some embodiments, R¹ and R² together form the following cyclic group,wherein the asterisks indicate the points of ring fusion to ring A, andeach cyclic group is optionally substituted by R^(d):

In some embodiments, R¹ and R² together with the atoms to which they areattached to form the following cyclic group, wherein the asterisksindicate the points of ring fusion to ring A, and each cyclic group isoptionally substituted by R^(d):

In some embodiments, R¹ and R² together form an unsubstituted cyclicgroup. In some embodiments, R¹ and R² together with the atoms to whichthey are attached to form an unsubstituted 6-membered heterocyclylgroup.

In some embodiments, ring A is selected from the group consisting of:

wherein each m is independently 0, 1, 2 or 3.

In some embodiments, ring A is

In some embodiments, ring A is selected from the group consisting of:

In some embodiments, R^(d) is selected from the group consisting of OH,CN, F, C₁-C₃ alkoxy, —O—C₁-C₃ alkyl-phenyl, NR^(a)R^(b), 4-6 memberedheterocyclyl, C(O)R^(g), C(O)₂R^(g) and C₁-C₆ alkyl optionallysubstituted by OH, CN, or 4-6 membered heterocyclyl. In someembodiments, R^(d) is C₁-C₆ alkyl optionally substituted by halogen. Insome embodiments, R^(d) is C₁-C₃ alkoxy (e.g., OCH₃).

In some embodiments, R^(c) and R^(d) are each independently selectedfrom the group consisting of halogen, —(X¹)₀₋₁—CN, —(X¹)₀₋₁—NO₂,—(X¹)₀₋₁—SF₅, —(X¹)₀₋₁—OH, —(X¹)₀₋₁—NH₂, —(X¹)₀₋₁—N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))(R^(1a)), —(X¹)₀₋₁—CF₃, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, oxo, —(X¹)₀₋₁—C₁-C₆alkyl, —(X¹)₀₋₁—C₃-C₇ cycloalkyl, —(X¹)₀₋₁-3-11 membered heterocyclyl(e.g., a 4-7 membered heterocycloalkyl or a 5-6 membered heteroaryl),—(X¹)₀₋₁—C₆-C₁₀ aryl, —C(═O)(X¹)₀₋₁-C₃-C₇ cycloalkyl, —C(═O)(X¹)₀₋₁-3-11membered heterocyclyl, —(X¹)₀₋₁—C(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—C(═Y¹)NH₂,—(X¹)₀₋₁—C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—C(═Y¹)OR^(1a),—(X¹)₀₋₁—C(═Y¹)OH, —(X¹)₀₋₁—N(H)C(═Y¹)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))C(═Y¹)(R^(1a)), —(X¹)₀₋₁—N(R^(b))C(═Y¹)(H),—(X¹)₀₋₁—N(H)C(═Y¹)OR^(1a), —(X¹)₀₋₁—N(R^(b))C(═Y¹)OR^(1a),—(X¹)₀₋₁—S(O)₁₋₂R^(1a), —(X¹)₀₋₁—N(H)S(O)₁₋₂R^(1a),—(X¹)₀₋₁—N(R^(1b))S(O)₁₋₂R^(1a), —(X¹)₀₋₁—S(O)₀₋₁N(H)(R^(1a)),—(X¹)₀₋₁—S(O)₀₋₁N(R^(1b))(R^(1a)), —(X¹)₀₋₁—S(O)₀₋₁NH₂,—(X¹)₀₋₁—S(═O)(═NR^(1b))R^(1a), —(X¹)₀₋₁—C(═Y¹)R^(1a), and—(X¹)₀₋₁—C(═Y¹)H, wherein X¹ is selected from the group consisting ofC₁-C₆ alkylene, C₁-C₆ heteroalkylene, C₂-C₆ alkenylene, C₂-C₆alkynylene, C₁-C₆ alkyleneoxy, C₃-C₇ cycloalkylene, 3-11 memberedheterocyclylene and phenylene; R^(1a) and R^(b) are each independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₃-C₇ cycloalkyl, 3-11 membered heterocyclyl, andphenyl, or R^(1a) and R^(b) when attached to the same nitrogen atom areoptionally combined to form a 3-11 membered heterocyclyl (e.g., a 4-7membered heterocycloalkyl or a 5-6 membered heteroaryl) comprising 0-3additional heteroatoms selected from N, O and S; Y¹ is O, NR^(1c) or Swherein R^(1c) is H or C₁-C₆ alkyl; wherein any portion of an R^(c) orR^(d) substituent, including R^(1a), R^(1b) and R^(1c), at eachoccurrence is each independently further substituted by from 0 to 4R^(f) substituents selected from the group consisting of halogen, CN,NO₂, OH, NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), oxo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, C₁-C₆ alkoxy,C₁-C₆ alkylthio, C₃-C₇ cycloalkyl, or 3-11 membered heterocyclyl (e.g.,a 4-7 membered heterocycloalkyl or a 5-6 membered heteroaryl).

In some embodiments of the compounds of formula (A), (Aa), (Aa-1),(Aa-2), (C), (Ca), (Ca-1) or (Ca-2), or a stereoisomer, tautomer,solvate, prodrug or salt thereof, n is 0, 1 or 2, and each R⁶ isindependently selected from the group consisting of F, Cl, OCH₃, CH₃ andCF₃. In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 1, and R⁶ is F.

In some embodiments, n is 1 and the ring bearing the R⁶ group (ring B)is:

In some embodiments, n is 2 and ring bearing the two independentlyselected R⁶ group (ring B) is:

In some embodiments of the compounds of formula (I), (II), (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1) or (Ba-2), or a stereoisomer,tautomer, solvate, prodrug or salt thereof, each R^(4a) and R^(4b) isindependently H or F; and R⁵ is C₁-C₆ alkyl optionally substituted byhalogen, OH, or C₁-C₆ alkoxy or C₃-C₄ cycloalkyl optionally substitutedby halogen, OH, or C₁-C₆ alkoxy. In some embodiments, each R^(4a) andR^(4b) is H. In some embodiments, each R^(4a) and R^(4b) is F. In someembodiments, R⁵ is C₁-C₆ alkyl optionally substituted by halogen, OH, orC₁-C₆ alkoxy. In some embodiments, R⁵ is C₃-C₄ cycloalkyl optionallysubstituted by halogen, OH, or C₁-C₆ alkoxy. In some embodiments, R⁵ isC₁-C₆ alkyl. In some embodiments, R⁵ is C₁-C₃ alkyl (e.g., methyl).

It is intended and understood that each and every variation of A₁-A₄,including variations of R¹ and R² where applicable, described forformula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1) or(Ba-2) may be combined with each and every variation of R^(4a), R^(4b)and R⁵ described for formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B),(Ba), (Ba-1) or (Ba-2) as if each and every combination is individuallydescribed. For example, in some embodiments of the compounds of formula(I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1) or (Ba-2), or astereoisomer, tautomer, solvate, prodrug or salt thereof, each R^(4a)and R^(4b) is H; R⁵ is methyl; and ring A is selected from the groupconsisting of:

In some embodiments, a heterocyclyl group contains one to three nitrogenatoms, one oxygen atom, or one sulfur atom, or any combination thereof.

In some embodiments, a compound of the present invention is defined asany one or more of the following:

In some embodiments, a compound of the present invention is defined asany one or more of the following:

Some embodiments provide a pharmaceutical composition comprising acompound of the present invention and a pharmaceutically acceptablecarrier, diluent or excipient. A compound or pharmaceutical compositiondescribed herein can be used in therapy, such as the treatment of acancer, a fibrotic condition, or an inflammatory condition (e.g., lupus,such as systemic lupus erythematosus, extra-renal lupus, or lupusnephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis,rheumatoid arthritis, dermatitis, endometriosis and transplantrejection). Also provided is the use of a compound or a pharmaceuticalcomposition described herein for the preparation of a medicament for thetreatment of an inflammatory condition (e.g., lupus, such as systemiclupus erythematosus, extra-renal lupus, or lupus nephritis, COPD,rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis,dermatitis, endometriosis and transplant rejection).

Also provided is a method for the treatment of an inflammatory conditionin a patient, comprising administering an effective amount of a compoundor pharmaceutical composition as described herein to the patient. Theinflammatory condition can be selected from the group consisting oflupus, such as systemic lupus erythematosus, extra-renal lupus, or lupusnephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis,rheumatoid arthritis, dermatitis, endometriosis and transplantrejection.

Also provided is a kit comprising a compound of formula (I), (II) (A),(Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1),(Ca-2), (D), (Da), (Da-1) or (Da-2), or a stereoisomer, tautomer,solvate, prodrug or salt thereof. Also provided is a kit comprising apharmaceutical composition comprising a compound of formula (I), (II)(A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1),(Ca-2), (D), (Da), (Da-1) or (Da-2), or a stereoisomer, tautomer,solvate, prodrug or salt thereof. The kit may further compriseinstructions for use, for example, according to a method describedherein. In some embodiments, the kit comprises packaging.

Further provided is a method of preparing a compound of formula (I):

wherein Q, A₁, A₂, A₃, A₅, A₆, A₇, A₈, R^(4a), R^(4b) and R⁵ are asdefined above, comprising:

(i) reacting a compound of formula (I-1):

wherein X is —Cl, —Br, —I, —OS(O)₂CF₃ (i.e. —OTf), —OC(O)CH₃ (i.e.—OAc), —OS(O)₂CH₃ (i.e. —OMs), —OS(O)₂(CH₃C₆H₄) (i.e. —OTs), or —N₂ ⁺(i.e. diazonium); and LG is a leaving group;

with a compound of formula (I-2):

to form a compound of formula (I-3):

and

(ii) converting the compound of formula (I-3) to the compound of formula(I).

In some embodiments of the method of preparation, Q is C.

In some embodiments, the method of preparing a compound of formula (I)further comprises the steps of:

(i) reacting a compound of formula (I-4):

wherein R^(4a), R^(4b) and R⁵ are as defined above,

with bis(trimethylsilyl)peroxide to form a compound of formula (I-5):

and

(ii) converting the compound of formula (I-5) to the compound of formula(I-2).

Also provided is a method of preparing a compound of formula (A):

wherein A₁, A₂, A₃, R^(4a), R^(4b), R⁵, R⁶ and n are as defined above,comprising:

(i) reacting a compound of formula (A-1):

wherein X is —Cl, —Br, —I, —OS(O)₂CF₃ (i.e. —OTf), —OC(O)CH₃ (i.e.—OAc), —OS(O)₂CH₃ (i.e. —OMs), —OS(O)₂(CH₃C₆H₄) (i.e. —OTs), or —N₂ ⁺(i.e. diazonium); and LG is a leaving group;

with a compound of formula (A-2):

to form a compound of formula (A-3):

and

(ii) converting the compound of formula (A-3) to the compound of formula(A).

In some of these embodiments, n is 0 (i.e., R⁶ is absent).

In some embodiments, the method of preparing a compound of formula (A)further comprises the steps of:

(i) reacting a compound of formula (A-4):

wherein R^(4a), R^(4b) and R⁵ are as defined above,

with bis(trimethylsilyl)peroxide to form a compound of formula (A-5):

and

(ii) converting the compound of formula (I-5) to the compound of formula(A-2).

In some embodiments of the method of making a compound of formula (I) or(A), each R^(4a) and R^(4b) is H; and R⁵ is methyl.

Further provided is a method of preparing a compound of formula (C):

wherein A₁, A₂, A₃, R⁶ and n are as defined above, comprising:

(i) reacting a compound of formula (C-1):

wherein X is —Cl, —Br, —I, —OS(O)₂CF₃ (i.e. —OTf), —OC(O)CH₃ (i.e.—OAc), —OS(O)₂CH₃ (i.e. —OMs), —OS(O)₂(CH₃C₆H₄) (i.e. —OTs), or —N₂ ⁺(i.e. diazonium); and LG is a leaving group; with a compound of formula(C-2):

to form a compound of formula (C-3):

and

(ii) converting the compound of formula (C-3) to the compound of formula(C).

In some of these embodiments, n is 0 (i.e., R⁶ is absent).

In some embodiments, the method of preparing a compound of formula (C)further comprises the steps of:

(i) reacting a compound of formula (1):

with bis(trimethylsilyl)peroxide to form a compound of formula (2):

and

(ii) converting the compound of formula (2) to the compound of formula(C-2).

The alpha-hydroxylation of the compound of formula (1) into the compoundof formula (2) was performed with bis(trimethylsilyl)peroxide. Morecommonly used reagents for the alpha-hydroxylation of amide and lactamcompounds are Davis reagent(3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine) and relatedN-sulfonyloxaziridine compounds. However, attempts to produce thecompound of formula (2) by reacting the compound of formula (1) withDavis reagent were unsuccessful. Inorganic peroxides (e.g., Vedejsreagent) are also useful for alpha-hydroxylation of amides and lactams.See, e.g., Davis, F. A. et al. Tetrahedron Lett. 1978, 19, 5171, Davis,F. A. et al. J. Org. Chem. 1984, 49, 3241, Davis, F. A. et al. J. Am.Chem. Soc. 1990, 112, 6679, and Davis, F. A. et al. Chem. Rev. 1992, 92,919; Pohmakotr, M. et al. Synth. Commun., 1988, 18(16-17), 2141-6;Wagnieres, O. et al. J. Am. Chem. Soc., 2014, 136(42), 15102-15108; andSears, J. E. et al. Org. Lett., 2015, 17(21), 5460-5463.

The coupling reaction between a compound of formula (I-1) or a variationthereof (e.g., formula (A-1) or (C-1)) and a compound of formula (I-2)or a variation thereof (e.g., a compound of (A-2) or (C-2)) may becarried out using coupling methods know in the art, for example, aSuzuki reaction or a Sonogashira reaction, and employing know reagentsand catalysts. In some embodiments, the method of preparation comprisesreacting a compound of formula (I-1) or a variation thereof (e.g.,formula (A-1) or (C-1)) with a compound of formula (I-2) or a variationthereof (e.g., a compound of (A-2) or (C-2)) in the presence of a metalcatalyst comprising a metal selected from Fe, Pd, Ni, Co, Cu andcombinations thereof. In some embodiments, the metal catalyst comprisesPd, Ni, Fe or Cu. In some embodiments, the catalyst comprises a Fe/Cumixture, a Pd/Cu mixture, a Ni/Cu mixture, or a Co/Cu mixture. In someembodiments, the catalyst comprises Pd (alone); Ni (alone); Fe (alone),or Cu (alone). These catalysts may be used with suitable ligands andreagents known in the art.

Persons of skill in the art are familiar with Suzuki reactions and thereagents employed in such reactions. See, e.g., Suzuki, J.Organometallic Chem., 576:147-168 (1999). Non-limiting examples ofpalladium catalysts include Pd(PPh₃)₄, Pd(OAc)₂ and Pd(PPh₃)₂Cl₂. Anon-limiting example of a copper catalyst is copper(II) acetate.Non-limiting examples of bases include sodium carbonate, potassiumcarbonate and cesium carbonate, or mixtures thereof. In someembodiments, copper(II) acetate and pyridine as the base are employedunder Chan-Lam coupling conditions, as is known in the art. For example,the carbon-nitrogen bond in an indazole or an aza-indazole can be formedusing Chan-Lam coupling conditions. A variety of organic solvents may beemployed, including toluene, THF, dioxane, 1,2-dichloroethane, DMF, DMSOand acetonitrile. Reaction temperatures vary depending on conditions buttypically range from room temperature to 150° C.

Reagents, catalysts and ligands employed in Sonogashira reactions areknown in the art, see, e.g., Rafael Chinchilla, Carmen Nájera, Chem.Soc. Rev., 2011, 40:5084-5121, and Marc Schilz, Herbert Plenio, J. Org.Chem., 2012, 77 (6):2798-2807.

Leaving groups (LG) useful in the synthetic methods described hereininclude but are not limited to alkoxy (e.g., —OCH₃), halogen (e.g., —F,−Cl, —Br, —I), —CN, —O-heteroaryl, (e.g., —O-(benzotriazol-1-yl) and—O—(N-succinimidyl)), —O-aryl (e.g., —OC₆F₅), N-imidazolyl, —O-acyl, andthiol. Other suitable leaving groups (LG) know in the art may also beused in the method, for example, leaving groups described in Greene'sProtective Groups in Organic Synthesis 4^(th) edition,Wiley-Interscience, New York, 2006.

In some embodiments, the method of preparation further comprises stepsof making a compound of formula (I-1) or a variation thereof (e.g.,formula (A-1) or (C-1)). In some embodiments, the method furthercomprises steps of making a compound of formula (I-2) or a variationthereof (e.g., a compound of (A-2) or (C-2)).

Synthetic intermediate of formula (I-2) or (A-2) or (C-2) may besynthesized using methods known in the art (see, e.g., Angew. Chem.Int'l Ed., 2015, 40:11826-11829.) and synthetic procedures describedherein. For example, the compound of formula (C-2) may be synthesizedaccording to Scheme 1 or 2.

Compound of formula (I-2) where R^(4a) and R^(4b) are F may besynthesized according to processes similar to those in Scheme 1 usingtert-butyl 6,6-difluoro-2-azabicyclo[3.1.0]hexane-2-carboxylate as astarting material, or Scheme 2 using 2,2-difluorocyclopropan-1-amine asa starting material. The difluoro compound of formula (I-2) may bereacted with a compound of formula (I-1) to product compounds of formula(I) where R^(4a) and R^(4b) are F, or a salt there of, for example,Compound Nos. 8-12, or a salt thereof.

In some embodiments, the invention provides a compound selected fromcompounds in Table 1, or a stereoisomer, tautomer, solvate, prodrug orsalt thereof. In some embodiments, provided is a compound selected fromcompounds in Table 1, or a stereoisomer, tautomer, or salt thereof. Theinvention also intends non-stereo-specific forms of the compoundsdepicted in Table 1, or a mixture of stereoisomers thereof, or saltsthereof.

TABLE 1 Compound No. Structure Name 1

1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide 2

1-(3-(((1S,4R,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide 3

3-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2- azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1- carboxamide 4

1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-7-methoxyimidazo[1,5-a]pyridine-3-carboxamide 5

3-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2- azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1- carboxamide 6

5-amino-2-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4- yl)ethynyl)phenyl)thiazole-4-carboxamide7

4-(2-fluoro-5-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1-methyl-1H-imidazole-2-carboxamide 8

1-(3-((6,6-difluoro-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide 9

1-(3-((6,6-difluoro-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4- yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide 10

1-(3-((6,6-difluoro-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-7-methoxyimidazo[1,5-a]pyridine-3-carboxamide 11

3-(3-((6,6-difluoro-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4- yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1-carboxamide 12

5-amino-2-(3-((6,6-difluoro-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4- yl)ethynyl)phenyl)thiazole-4-carboxamide

In some embodiments, the invention provides a compound in the Examples.

In some embodiments, the compound is selected from Compound Nos. 1-12,or a salt thereof. In some embodiments, the compound is selected fromCompound Nos. 1-5, or a salt thereof. In some embodiments, the compoundis selected from Compound No. 6, or a salt thereof.

The 4-alkynyl-4-hydroxy-2-azabicyclo[3.1.0]hexan-3-one compounds of thepresent invention demonstrate superior metabolic stability to thecorresponding 3-alkynyl-3-hydroxy-pyrrolidin-2-one analogs. For example,Compound Nos. 1-6 were found to improve metabolic stability and havegenerally lower clearance in human liver microsomes and humanhepatocytes than the corresponding comparator compounds shown in Table2. Thus the 2-azabicyclo[3.1.0]hexan-3-one NIK inhibitor compounds ofthe present invention can be advantageous in use for treating a diseaseor condition in a human subject responsive to NIK inhibition (e.g., aninflammatory condition or a cancer). Metabolic stability of drugcompounds can be evaluated using known methods, for example, in humanliver microsomes and human hepatocytes, following protocols described inHalladay, et al. Drug Metabol. Lett. 2007, 1:67-72; Hallifax, et al.Drug Metabol. Disposition, 2005, 33:1852-1858; and Liu, et al. DrugMetabol. Disposition, 2011, 39:1840-1849.

TABLE 2 Compound No. Structure 1

2

3

4

5

6

C-1

C-1

C-3

C-4

C-5

C-6

Synthesis of NIK Inhibitors

Methods for preparing intermediates and compounds of the presentinvention are presented in the Examples section below. Those skilled inthe art will appreciate that other synthetic routes may be used tosynthesize the inventive compounds. Although specific starting materialsand reagents are depicted in the Schemes and discussed below, otherstarting materials and reagents can be easily substituted to provide avariety of derivatives or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

The starting materials are generally available from commercial sourcessuch as Aldrich Chemicals (Milwaukee, Wis.) or are readily preparedusing methods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), orBeilstein's Handbuch der organishcen chemie, 4, Aufl. Ed.Springer-Verlag, Berlin including supplements also included via theBeilstein online database.

In preparing a compound of formula (I), (II), (A), (Aa), (Aa-1), (Aa-2),(B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1)or (Da-2), protection of remote functionality (e.g., primary orsecondary amine) of intermediates may be necessary. The need for suchprotection will vary depending on the nature of the remote functionalityand the conditions of the preparation methods. The need for suchprotection is readily determined by one skilled in the art. Exemplaryprotecting groups are provided herein. For a general description ofprotecting groups and their use, see P. G. M. Wuts and T. W. Greene,Greene's Protective Groups in Organic Synthesis 4^(th) edition,Wiley-Interscience, New York, 2006.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn or supercritical fluid chromatography.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S., Stereochemistry of OrganicCompounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,J. Chromatogr., 113(3):283-302 (1975)). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: DrugStereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reaction of enantiomerically purechiral bases such as brucine, quinine, ephedrine, strychnine,α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetriccompounds bearing acidic functionality, such as carboxylic acid andsulfonic acid. The diastereomeric salts may be induced to separate byfractional crystallization or ionic chromatography. For separation ofthe optical isomers of amino compounds, addition of chiral carboxylic orsulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelicacid, or lactic acid can result in formation of the diastereomericsalts.

Alternatively, the substrate to be resolved is reacted with oneenantiomer of a chiral compound to form a diastereomeric pair (Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons,Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem.47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). Bymethod (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (Chiral LiquidChromatography W. J. Lough, Ed., Chapman and Hall, New York, (1989);Okamoto, J. of Chromatogr. 513:375-378 (1990)). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism. The absolute stereochemistry of chiral centersand enantiomers can be determined by x-ray crystallography.

Positional isomers, for example E and Z forms, of compounds of formula(I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C),(Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) and (Da-2), and intermediatesfor their synthesis, may be observed by characterization methods such asNMR and analytical HPLC. For certain compounds where the energy barrierfor interconversion is sufficiently high, the E and Z isomers may beseparated, for example by preparatory HPLC.

Pharmaceutical Compositions and Administration

The compounds with which the invention is concerned are NIK kinaseinhibitors, and are useful in the treatment of several diseases, forexample, cancer or inflammatory conditions.

The invention also provides for compositions and medicaments comprisinga compound of formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba),(Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), orany variation thereof detailed herein and at least one pharmaceuticallyacceptable carrier, diluent or excipient. The compositions of theinvention can be used for inhibiting NF-kB signaling activity in mammals(e.g., human patients), by for example, inhibiting NIK activity.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions (or medicaments) comprising a compound of formula (I),(II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca),(Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or any variation thereofdetailed herein and a pharmaceutically acceptable carrier, diluent orexcipient. In another embodiment, the invention provides for preparingcompositions (or medicaments) comprising compounds of the invention. Inanother embodiment, the invention provides for administering a compoundof formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1),(Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or anyvariation thereof detailed herein and compositions comprising a compoundof formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1),(Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or anyvariation thereof detailed herein to a mammal (e.g., a human patient) inneed thereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit NIK activity as required to preventor treat the undesired disease or disorder, such as for example,neurodegeneration, amyloidosis, formation of neurofibrillary tangles, orundesired cell growth (e.g., cancer cell growth). For example, suchamount may be below the amount that is toxic to normal cells, or themammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, such as 0.3 to 15 mg/kg/day. The daily doesis, in certain embodiments, given as a single daily dose or in divideddoses two to six times a day, or in sustained release form. In the caseof a 70 kg adult human, the total daily dose will generally be fromabout 7 mg to about 1,400 mg. This dosage regimen may be adjusted toprovide the optimal therapeutic response. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compositions comprising a compound of formula (I), (II), (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1), (Da-2), or any variation thereof detailed herein arenormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition. A typical formulation is prepared bymixing a compound of the present invention and a diluent, carrier orexcipient. Suitable diluents, carriers and excipients are well known tothose skilled in the art and are described in detail in, e.g., Ansel,Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug DeliverySystems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,Alfonso R., et al. Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press,2005. The formulations may also include one or more buffers, stabilizingagents, surfactants, wetting agents, lubricating agents, emulsifiers,suspending agents, preservatives, antioxidants, opaquing agents,glidants, processing aids, colorants, sweeteners, perfuming agents,flavoring agents, diluents and other known additives to provide anelegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., a compound offormula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2),(C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or any variationthereof detailed herein) can also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacrylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philadelphia, Pa.

Sustained-release preparations of a compound of the invention can beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba),(Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), orany variation thereof detailed herein, which matrices are in the form ofshaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philadelphia, Pa. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients.

In general the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers,diluents or excipients or finely divided solid carriers, diluents orexcipients, or both, and then, if necessary, shaping the product. Atypical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. The formulations can beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound of the present invention is typicallyformulated into pharmaceutical dosage forms to provide an easilycontrollable dosage of the drug and to enable patient compliance withthe prescribed regimen.

In one example, compounds of formulae (I), (II), (A), (Aa), (Aa-1),(Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da),(Da-1) and (Da-2) may be formulated by mixing at ambient temperature atthe appropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers. The pH of the formulation dependsmainly on the particular use and the concentration of compound, buttypically ranges anywhere from about 3 to about 8. In one example, acompound of formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba),(Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), orany variation thereof detailed herein is formulated in an acetatebuffer, at pH 5. In another embodiment, the compounds of formulae (I),(II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca),(Ca-1), (Ca-2), (D), (Da), (Da-1) and (Da-2) are sterile. The compoundmay be stored, for example, as a solid or amorphous composition, as alyophilized formulation or as an aqueous solution.

Formulations of a compound of the invention suitable for oraladministration can be prepared as discrete units such as pills,capsules, cachets or tablets each containing a predetermined amount of acompound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention intended for oral use can be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions can contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients can be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,calcium or sodium phosphate; granulating and disintegrating agents, suchas maize starch, or alginic acid; binding agents, such as starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc. Tablets can be uncoated or can be coated by knowntechniques including microencapsulation to delay disintegration andadsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax can beemployed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention, or any rangederivable therein, compounded with about 5-30 mg anhydrous lactose,about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone(PVP) K30, and about 1-10 mg magnesium stearate. The powderedingredients are first mixed together and then mixed with a solution ofthe PVP. The resulting composition can be dried, granulated, mixed withthe magnesium stearate and compressed to tablet form using conventionalequipment. An example of an aerosol formulation can be prepared bydissolving the compound, for example 5-400 mg, of the invention in asuitable buffer solution, e.g., a phosphate buffer, adding a tonicifier,e.g., a salt such sodium chloride, if desired. The solution may befiltered, e.g., using a 0.2 micron filter, to remove impurities andcontaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base.

If desired, the aqueous phase of the cream base can include a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400) and mixtures thereof. Thetopical formulations can desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of this invention can be constitutedfrom known ingredients in a known manner. While the phase can comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of a compound of the invention contain the activematerials in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients include a suspending agent, such assodium carboxymethylcellulose, croscarmellose, povidone,methylcellulose, hydroxypropyl methylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension canalso contain one or more preservatives such as ethyl or n-propylp-hydroxybenzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Formulations of a compound of the invention can be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension can be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation can also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that can be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils can conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid can likewise be used in the preparation ofinjectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of disorders as described below.

Formulations suitable for vaginal administration can be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

Indications and Methods of Treatment

The compounds of formulae (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B),(Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) and(Da-2), inhibit the activity of NIK. Accordingly, in another aspect ofthe invention the compounds of the invention can be used for thetreatment of diseases and disorders in a mammal, for example a humanpatient, in which the inhibition of NIK in the patient would betherapeutically effective. For example, the compounds of the inventionare useful for the treatment of diseases or disorders in a mammal (e.g.,a human patient) associated with over-active or undesired NF-kBsignaling through, for example, the over-activation of NIK. In oneembodiment, the compounds of the invention are used to inhibit theactivity of NIK, for example in an in vitro assay setting, by contactingsaid compound of formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B),(Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1),(Da-2), or any variation thereof detailed herein with NIK. For example,compounds of formulae (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba),(Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) and (Da-2)can be used as a control compound in an in vitro assay setting.

In another embodiment, the compounds of the invention are used toinhibit the undesired signaling of NF-kB, e.g., in an cell proliferationassay, by introducing into a cell a compound of formula (I), (II), (A),(Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1),(Ca-2), (D), (Da), (Da-1), (Da-2), or any variation thereof detailedherein. In another embodiment, the present invention provides thetreatment of diseases or disorders in a mammal (e.g., human patient)associated with over-active or undesired NF-kB signaling (e.g., cancer,inflammatory diseases, among others) said method comprisingadministering to a mammal (e.g., a human patient) in need thereof atherapeutically effective amount of a compound of the invention.

Diseases and disorders treatable according to the methods of thisinvention include, cancer, inflammatory conditions, fibrotic conditions,autoimmune disease and proliferation induced after medical procedures(e.g., arthritis, graft rejection, inflammatory bowel disease, cellproliferation induced after surgery angioplasty, among others). In oneembodiment, a mammal (e.g., a human patient) is treated with a compoundof the invention and a pharmaceutically acceptable carrier, adjuvant, orvehicle, wherein said compound of the invention is present in an amountto inhibit NF-kB signaling through, for example, but not limited to,inhibition of NIK.

In one embodiment, a compound of the invention can be used in thetreatment of cell proliferative disorders.

In one embodiment of the invention, cancers that may be treated by thecompounds of formulae (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba),(Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) and (Da-2)are selected from the group consisting of Lung (bronchogenic carcinoma(non-small cell lung); Gastrointestinal—rectal, colorectal and colon;Genitourinary tract—kidney (papillary renal cell carcinoma); andskin—head and neck squamous cell carcinoma.

In one embodiment, compounds of formulae (I), (II), (A), (Aa), (Aa-1),(Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da),(Da-1) and (Da-2) can be used for the treatment of a cancer selectedfrom the group consisting of head and neck squamous cell carcinomas,histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer,non-small cell lung cancer, pancreatic cancer, papillary renal cellcarcinoma, liver cancer, gastric cancers, colon cancer, leukemias,lymphomas, multiple myeloma, glioblastomas and breast carcinoma.

In one embodiment, compounds of formulae (I), (II), (A), (Aa), (Aa-1),(Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da),(Da-1) and (Da-2) can be used for the treatment of a cancer selectedfrom the group consisting of histiocytic lymphoma, lung adenocarcinoma,small cell lung cancer, pancreatic cancer, liver cancer, gastric cancer,colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas andbreast carcinoma.

In one embodiment, compounds of formulae (I), (II), (A), (Aa), (Aa-1),(Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da),(Da-1) and (Da-2) can be used for the treatment of cancer selected fromthe group consisting of lymphomas, leukemias and multiple myeloma.

In one embodiment, the invention provides for the preparation of amedicament comprising a compound of formula (I), (II), (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1), (Da-2), or any variation thereof detailed herein forthe treatment of lymphoma, leukemia or multiple myeloma.

In one embodiment, the invention provides for the treatment of lymphoma,leukemia or multiple myeloma, which method comprises administering aneffective amount of a compound of formula (I), (II), (A), (Aa), (Aa-1),(Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da),(Da-1), (Da-2), or any variation thereof detailed herein.

In one embodiment, compounds of the invention are useful for thetreatment of inflammatory diseases and conditions including, but notlimited to, lupus (including systemic lupus erythematosus, extra-renallupus and lupus nephritis), asthma, COPD, rhinitis, multiple sclerosis,IBD, arthritis, gastritis, rheumatoid arthritis, dermatitis,endometriosis, transplant rejection, cardiac infarction, Alzheimer'sdiseases, diabetes Type II, inflammatory bowel disease, sepsis,arthrosclerosis, and atherosclerosis.

In one embodiment, the invention provides for the use of a compound offormula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2),(C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or any variationthereof detailed herein for the treatment of an inflammatory condition.

In one embodiment, the invention provides for the use of a compound offormula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2),(C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or any variationthereof detailed herein for the preparation of a medicament for thetreatment of an inflammatory condition.

In one embodiment, the invention provides for a compound of formula (I),(II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca),(Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or any variation thereofdetailed herein for the treatment of an inflammatory condition.

In one embodiment, the invention provides for a method for the treatmentof an inflammatory condition, which method comprises administering aneffective amount of a compound of formula (I), (II), (A), (Aa), (Aa-1),(Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da),(Da-1), (Da-2), or any variation thereof detailed herein to a patient inneed thereof.

In one embodiment, the invention provides for the treatment of aninflammatory condition selected from the group consisting of lupus(including systemic lupus erythematosus, extra-renal lupus and lupusnephritis), COPD, rhinitis, multiple sclerosis, IBD, arthritis,rheumatoid arthritis, dermatitis, endometriosis and transplantrejection, which method comprises administering an effective amount of acompound of formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba),(Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), orany variation thereof detailed herein.

In one embodiment, compounds of the invention are useful for thetreatment of fibrotic diseases and conditions including, but not limitedto, fibrosis, endomyocardial fibrosis, pulmonary fibrosis, pulmonaryfibrosis secondary to sclerosis, cystic fibrosis, idiopathic pulmonaryfibrosis and hepatic fibrosis.

In one embodiment, the invention provides for the use of a compound offormula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2),(C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or any variationthereof detailed herein for the treatment of a fibrotic condition.

In one embodiment, the invention provides for the use of a compound offormula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2),(C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or any variationthereof detailed herein for the preparation of a medicament for thetreatment of a fibrotic condition.

In one embodiment, the invention provides for a compound of formula (I),(II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca),(Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or any variation thereofdetailed herein for the treatment of an inflammatory condition.

In one embodiment, the invention provides for a method for the treatmentof a fibrotic condition, which method comprises administering aneffective amount of a compound of formula (I), (II), (A), (Aa), (Aa-1),(Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da),(Da-1), (Da-2), or any variation thereof detailed herein to a patient inneed thereof.

In one embodiment, the invention provides for the treatment of afibrotic selected from the group consisting of fibrosis, endomyocardialfibrosis, pulmonary fibrosis, pulmonary fibrosis secondary to sclerosis,cystic fibrosis, idiopathic pulmonary fibrosis and hepatic fibrosis,which method comprises administering an effective amount of a compoundof formula (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B), (Ba), (Ba-1),(Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1), (Da-2), or anyvariation thereof detailed herein.

Combinations

The compounds of formulae (I), (II), (A), (Aa), (Aa-1), (Aa-2), (B),(Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2), (D), (Da), (Da-1) and(Da-2) may be employed alone or in combination with other therapeuticagents for treatment. In one embodiment, compounds of this invention maybe employed alone or in combination with chemotherapeutic agents. In oneembodiment, compounds of this invention may be employed alone or incombination with anti-inflammatory agents. In one embodiment, compoundsof this invention may be employed alone or in combination withanti-fibrotic agents. The compounds of the present invention can be usedin combination with one or more additional drugs, for example ananti-inflammatory compound, an anti-fibrotic compound or anti-cancercompounds, that work by a different mechanism of action. The secondcompound of the pharmaceutical combination formulation or dosing regimenpreferably has complementary activities to the compound of thisinvention such that they do not adversely affect each other. Suchmolecules are suitably present in combination in amounts that areeffective for the purpose intended. The compounds may be administeredtogether in a unitary pharmaceutical composition or separately and, whenadministered separately this may occur simultaneously or sequentially inany order. Such sequential administration may be close in time or remotein time.

In certain embodiments, a compound of formula (I), (II), (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1), (Da-2), or any variation thereof detailed herein iscombined in a pharmaceutical combination formulation, or dosing regimenas combination therapy, with a second therapeutic compound that hasanti-inflammatory, anti-fibrotic or anti-cancer properties or that isuseful for treating an inflammation, fibrotic condition, immune-responsedisorder, or hyperproliferative disorder (e.g., cancer). The secondtherapeutic agent may be a NSAID (Non-Steroidal Anti-Inflammatory Drug)or other anti-inflammatory agent. The second therapeutic agent may be ananti-fibrotic agent. The second therapeutic agent may be achemotherapeutic agent. In one embodiment, a pharmaceutical compositionof this invention comprises a compound of formula (I), (II), (A), (Aa),(Aa-1), (Aa-2), (B), (Ba), (Ba-1), (Ba-2), (C), (Ca), (Ca-1), (Ca-2),(D), (Da), (Da-1), (Da-2), or any variation thereof detailed herein incombination with a therapeutic agent such as an NSAID.

EXAMPLES

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as defined by the claims.

The chemical reactions in the Examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, e.g.,by appropriately protecting interfering groups, by utilizing othersuitable reagents known in the art other than those described, or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

In some cases, stereoisomers are separated to give single enantiomers ordiastereomers as single, unknown stereoisomers, and are arbitrarilydrawn as single isomers. Where appropriate, information is given onseparation method and elution time and order.

Example A Synthesis of4-ethynyl-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one

Step 1: Synthesis of tert-butyl 2-azabicyclo[3.1.0]hexane-2-carboxylate

A solution of sodium carbonate in water (79 ml, 79 mmol, 1 mol/l) andsolution of di-tert-butyl dicarbonate (9060 mg, 41.5 mmol) in 10 ml oftetrahydrofuran was added dropwise simultaneously to a solution of2-aza-bicyclo[3.1.0]hexane hydrochloride (4410 mg, 36.9 mmol) in amixture of water and tetrahydrofuran (1:1, 90 ml). The mixture wasstirred for 2 hours, extracted with ethyl acetate, the organic extractswere washed with water, brine, dried over magnesium sulfate andconcentrated. The residue was purified on a 40 g silica gel columneluting with 20% of ethyl acetate in heptane to give 6230 mg (92%) ofthe title compound. LC-MS (ES, m/z): 367 [2M+H]⁺.

Step 2: Synthesis of tert-butyl3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate

A solution of dioxoruthenium hydrate (2055 mg, 13.6 mmol) and sodiumperiodate (36.4 g, 170 mmol) in 500 ml of water was added portionwise toa mixture of tert-butyl 4-azabicyclo[3.1.0]hexane-4-carboxylate (6230mg, 34.0 mmol) in 650 ml of ethyl acetate. The mixture was vigorouslystirred for 20 h. The black precipitate was filtered out, the filtratemixed with 250 ml of 5% aqueous Na₂S₂O₃ and organic layer separated. Theorganic extracts were washed with water, brine, dried over MgSO₄ andconcentrated. The residue—heavy oil—solidified upon standing to give5557 mg (83%) of the title compound. LC-MS (ES, m/z): 142[M-i-Butylene+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 3.61-3.53 (m, 1H),2.94-2.84 (m, 1H), 2.52 (dt, J=18.8, 1.1 Hz, 1H), 1.55 (s, 9H),1.52-1.46 (m, 1H), 1.06-0.96 (m, 1H), 0.49-0.40 (m, 1H).

Step 3: Synthesis of 2-azabicyclo[3.1.0]hexan-3-one

A solution of HCl in dioxane (20 mL, 80 mmol, 4.0 mol/L) was addeddropwise to a stirred solution of tert-butyl3-oxo-4-azabicyclo[3.1.0]hexane-4-carboxylate (1973 mg, 10.0 mmol) in 40ml of dichloromethane. The stirring continued for 2 hours after CO₂ceased to evolve. The reaction mixture was concentrated in vacuum, theresidue redissolved in dichloromethane and concentrated again. Theoperation was repeated two more times to give 946 mg (97%) of the titlecompound. LC-MS (ES, m/z): 195 [2M+H]⁺.

Step 4: Synthesis of 2-methyl-2-azabicyclo[3.1.0]hexan-3-one

A mixture of 4-azabicyclo[3.1.0]hexan-3-one (900 mg, 9.3 mmol) andcesium carbonate (5120 mg, 15.7 mmol) in acetonitrile (40 ml) wasstirred for 15 min and then iodomethane (0.87 ml, 14 mmol) was added tothe suspension. The mixture was heated at 70-80° C. in a sealed vial for12 hours. The resulting mixture was cooled to the ambient temperatureand filtered. The filtrate was concentrated in vacuum to give 873 mg(85%) of the title compound. LC-MS (ES, m/z): 223 [2M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 3.04-2.95 (m, 1H), 2.90 (s, 3H), 2.83-2.72 (m, 1H),2.36 (dt, J=17.8, 1.1 Hz, 1H), 1.55-1.45 (m, 1H), 0.90-0.83 (m, 1H),0.34-0.31 (m, 1H).

Step 5: Synthesis of 4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one

Lithium bis(trimethylsilyl)amide in tetrahydrofuran (7.5 ml, 7.5 mmol, 1mol/1) was added dropwise to a mixture of4-methyl-4-azabicyclo[3.1.0]hexan-3-one (556 mg, 5.0 mmol) andbis(trimethylsilyl)peroxide (3.3 ml, 15 mmol) in tetrahydrofuran (15 ml)at −76° C. The mixture was stirred at this temperature for 1 hour,allowed to warm up to −30° C. and left at this temperature for 1 hour.The mixture was quenched with 1 M aqueous HCl and stirred for 30 min.The resulting mixture was extracted with pentane 3 times. The aqueouslayer was neutralized to pH 7 by addition of saturated aqueous NaHCO₃and concentrated in vacuum to dryness. The dry residue was extractedwith dichloromethane, filtered and the filtrate concentrated to give 498mg (78%) of the title compound as a yellowish oil crystallizing uponstanding. LC-MS (ES, m/z): 255 [2M+H]⁺, 128 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 4.86 (d, J=4.3 Hz, 1H), 4.17 (dd, J=4.3, 1.6 Hz, 1H),3.12-3.01 (m, 1H), 2.91 (s, 3H), 1.72-1.63 (m, 1H), 1.02-0.92 (m, 1H),0.39-0.31 (m, 1H).

Step 6: Synthesis of 2-methyl-2-azabicyclo[3.1.0]hexane-3,4-dione

Dess-Martin periodinane (1994 mg, 4.7 mmol) was added portionwise to asolution of 2-hydroxy-4-methyl-4-azabicyclo[3.1.0]hexan-3-one (498 mg,3.9169 mmol) in dichloromethane (25 ml). The mixture was stirred atambient temperature for 1 hour. The resulting mixture was concentratedin vacuum, the residual acetic acid was coevaporated with heptane twice,and the semisolid residue was redissolved in dichloromethane, filteredand loaded on a 24 g column eluting with 0-100% gradient of ethylacetate in heptane to give 320 mg (65%) of a title compound. LC-MS (ES,m/z): 251 [2M+H]⁺, 126 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ3.72-3.66 (m, 1H), 3.11 (s, 3H), 2.36-2.27 (m, 1H), 1.64-1.55 (m, 1H),1.55-1.48 (m, 1H).

Step 7: Synthesis of4-ethynyl-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one

A solution of 4-methyl-4-azabicyclo[3.1.0]hexane-2,3-dione (318 mg, 2.5mmol) in 8 ml of tetrahydrofuran was added dropwise to abromo(ethynyl)magnesium (10.0 mL, 5 mmol, 0.5 mol/L) in tetrahydrofuranat −76° C. The mixture was stirred for 1 hour. The mixture was quenchedwith 5 ml of saturated aqueous NH₄Cl and after warming to ambienttemperature extracted four times with 10 ml of ethyl acetate. Theorganic extracts were dried with MgSO₄ and concentrated to give 213 mg(55%) of the title compound as mixture of diastereomers (3:1 by NMR).LC-MS (ES, m/z): 303 [2M+H]⁺, 152 [M+H]⁺.

Example A-bis Alternate Synthesis of4-ethynyl-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one

Step 1: Synthesis of 2-chloro-N-cyclopropyl-N-methylacetamide

To a 5000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a solution ofN-methylcyclopropanamine hydrochloride (90 g, 836.57 mmol, 1.00 equiv)in dichloromethane (3000 mL) followed by the addition of triethylamine(295.9 g, 2.92 mol, 3.50 equiv) dropwise with stirring in an ice/saltbath. To this was added 2-chloroacetyl chloride (103.2 g, 913.74 mmol,1.10 equiv) dropwise with stirring at −20° C. The resulting solution wasstirred overnight at 25° C. The reaction mixture was cooled with awater/ice bath and then quenched by the addition of 1000 mL of water.The resulting solution was extracted with 2×1000 mL of dichloromethane.The organic layers were combined, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was applied onto a silica gelcolumn eluted with ethyl acetate/petroleum ether (1:5) to afford 110 g(89%) of 2-chloro-N-cyclopropyl-N-methylacetamide as light yellow oil.¹H NMR (300 MHz, Chloroform-d) δ 4.32 (s, 2H), 2.98 (s, 3H), 2.84-2.72(m, 1H), 0.97-0.84 (m, 4H).

Step 2: Synthesis of 2-methyl-2-azabicyclo[3.1.0]hexan-3-one

To a 3000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of argon was placed2-chloro-N-cyclopropyl-N-methylacetamide (22.2 g, 150.40 mmol, 1.00equiv), bis(dibenzylideneacetone)palladium(0) (2.6 g, 4.48 mmol, 0.03equiv),(3aR,8aR)-4,4,8,8-tetrakis(3,5-di-tert-butylphenyl)-2,2-dimethyl-6-phenyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine(9.2 g, 9.02 mmol, 0.06 equiv), adamantane-1-carboxylic acid (810 mg,4.49 mmol, 0.03 equiv), Cs₂CO₃ (73.5 g, 225 mmol, 1.50 equiv), 4 Åmolecular sieves (22.2 g) and toluene (1500 mL). The resulting mixturewas stirred overnight at 70° C. in an oil bath. This reaction wasrepeated 3 times. The reaction mixture was cooled to room temperature.The solids were filtered out and washed with 1×2 L of ethyl acetate. Thefiltrate was concentrated under vacuum. The crude product was purifiedby distillation under reduced pressure (10 mm Hg) and the fraction wascollected at 80° C. to afford 51 g (76%) of2-methyl-2-azabicyclo[3.1.0]hexan-3-one as light yellow liquid. ¹H NMR(300 MHz, Chloroform-d) δ 2.99-2.96 (m, 1H), 2.92 (s, 3H), 2.74-2.70 (m,1H), 2.35 (d, J=18.0, 1H), 1.52-1.43 (m, 1H), 0.89-0.85 (m, 1H),0.32-0.29 (m, 1H).

Step 3: Synthesis of2-methyl-4,4-bis(methylthio)-2-azabicyclo[3.1.0]hexan-3-one

To a 1000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of argon was placed2-methyl-2-azabicyclo[3.1.0]hexan-3-one (11 g, 98.97 mmol, 1.00 equiv)and tetrahydrofuran (500 mL) followed by the addition of lithiumdiisopropylamide (75 mL, 1.50 equiv) dropwise with stirring at −30° C.in 1 hour. To this was added (methanesulfonylsulfanyl)methane (19 g,150.56 mmol, 1.50 equiv) dropwise with stirring at −30° C. in 2 hours.The resulting solution was stirred overnight at 25° C. This reaction wasrepeated for 3 times. The reaction mixture was cooled with a water/icebath and then quenched by the addition of 800 mL of saturated aqueousNH₄Cl. The resulting solution was extracted with 3×1000 mL of ethylacetate and the organic layers were combined, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column eluted with ethyl acetate/petroleum ether(1:10) to afford 44 g (55%) of2-methyl-4,4-bis(methylsulfanyl)-2-azabicyclo[3.1.0]hexan-3-one asyellow oil. ¹H NMR (300 MHz, Chloroform-d) δ 3.21-3.14 (m, 1H), 2.91 (s,3H), 2.32 (s, 3H), 2.24 (s, 3H), 2.70-2.62 (m, 1H), 1.04-0.97 (m, 1H),0.79-0.82 (m, 1H).

Step 4: Synthesis of 2-methyl-2-azabicyclo[3.1.0]hexane-3,4-dione

To a 3-L 4-necked round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed2-methyl-4,4-bis(methylsulfanyl)-2-azabicyclo[3.1.0]hexan-3-one (22 g,108.20 mmol, 1.00 equiv) and acetonitrile (2000 mL), water (200 mL)followed by the addition of (bis(trifluoroacetoxy)iodo)benzene (92.9 g,216.03 mmol, 2.00 equiv) in portions. The resulting solution was stirredfor 2 hours at 0° C. in an ice/salt bath. This reaction was repeatedonce. The reaction was then quenched by the addition of 1000 mL ofsaturated aqueous NaHCO₃. The resulting solution was extracted with 4×1L of chloroform and the organic layers were combined and dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column eluted with ethyl acetate/petroleumether (4:1) to afford 19 g (70%) of2-methyl-2-azabicyclo[3.1.0]hexane-3,4-dione as a light yellow solid. ¹HNMR (300 MHz, Chloroform-d) δ 3.75-3.69 (m, 1H), 3.14 (s, 3H), 2.38-2.32(m, 1H), 1.66-1.53 (m, 2H).

Step 5: Synthesis of4-ethynyl-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one

To a 1000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of argon was placed bromo(ethynyl)magnesium (0.5 M)(256 mL) followed by the addition of a solution of2-methyl-2-azabicyclo[3.1.0]hexane-3,4-dione (8 g, 63.94 mmol, 1.00equiv) in tetrahydrofuran (200 mL) dropwise with stirring at −78° C. andthen stirred for 1 hour at the same temperature. The resulting solutionwas stirred for 4 hours at −78 to 0° C. in a liquid nitrogen bath. Thisreaction was repeated once. The reaction mixture was cooled to −30° C.The reaction was then quenched by the addition of 400 mL of saturatedaqueous NH₄Cl. The resulting solution was extracted with 3×500 mL ofethyl acetate and the organic layers were combined, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column eluted with ethyl acetate/petroleum ether(4:1). The crude product was purified by re-crystallization from ethylacetate to afford 17 g (88%) of4-ethynyl-4-hydroxy-2-methyl-2-azabicyclo[3.1.0]hexan-3-one as a lightyellow solid. LC-MS (ES, m/z): 303 [2M+H]⁺, 152 [M+H]⁺.

Examples 1 and 2 Synthesis of1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

Step 1: Synthesis of methyl1-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

A mixture of methyl1-(3-bromophenyl)pyrazolo[3,4-b]pyridine-3-carboxylate (seeWO2015/025025) (150 mg, 0.45 mmol),2-ethynyl-2-hydroxy-4-methyl-4-azabicyclo[3.1.0]hexan-3-one (106 mg,0.70 mmol), bis(triphenylphosphine)palladium(II) chloride (51 mg, 0.07mmol) and triethylamine (0.39 mL, 2.8 mmol) in dimethylsulfoxide (10 ml)was degassed and heated in a sealed vial at 95° C. for 1 hour. Themixture was mixed with water and extracted with ethyl acetate. Theorganic extracts were washed with 1% aqueous citric acid, water, brine,dried over MgSO₄ and concentrated. The residue was purified on a 12 gsilica gel column eluting with 0-100% gradient of ethyl acetate inheptane to give 143 mg (79%) of the title compound as a mixture ofdiastereomers. LC-MS (ES, m/z): 403 [M+H]⁺.

Step 2: Synthesis of1-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

A mixture of methyl1-[3-[2-(2-hydroxy-4-methyl-3-oxo-4-azabicyclo[3.1.0]hexan-2-yl)ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxylate(143 mg, 0.36 mmol) and 6 ml of sat. ammonia in methanol was heated in asealed vial at 60° C. for 12 hours. The resulting mixture wasconcentrated, the residue redissolved in methanol and concentrated againto give 134 mg (97%) of the title compound as a mixture ofdiastereomers. LC-MS (ES, m/z): 388 [M+H]⁺.

Step 3: Isolation of1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

A mixture of diastereomers was subjected to a chiral separation bysupercritical fluid chromatography (SFC) to afford the four individualisomers.

SFC preparative conditions: Instrument: SFC PICLab PREP 100 (PIC 100SFC); Column: Chiralpak AD (150×21.1 mm, 5 m); Method: Isocratic (45%Mobile Phase B); Mobile Phase A: carbon dioxide; Mobile Phase B: Ethanolwith 0.1% NH₄OH; Flow rate: 70 mL/min; Pressure: 100 bars; Temperature:40° C.

Compound 1:1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide(31.7 mg, 23.7%). LC-MS (ES, m/z): 388 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.78 (dd, J=4.6, 1.7 Hz, 1H), 8.67 (dd, J=8.1, 1.7 Hz, 1H), 8.53-8.48(m, 2H), 8.25 (s, 1H), 7.71 (s, 1H), 7.64 (td, J=7.9, 0.8 Hz, 1H), 7.52(dd, J=8.1, 4.5 Hz, 1H), 7.49-7.45 (m, 1H), 6.47 (s, 1H), 3.38-3.31 (m,1H), 2.82 (s, 3H), 2.10-2.02 (m, 1H), 0.86 (ddd, J=8.4, 5.8, 4.7 Hz,1H), 0.64 (ddd, J=5.8, 4.7, 2.4 Hz, 1H). Supercritical FluidChromatography analytical conditions: Instrument: Waters ACQUITY UPC2System (Waters UPC2); Column: Chiralpak AD (50×4.6 mm, 3 μm); Method:Isocratic (40% Mobile Phase B); Mobile Phase A: carbon dioxide; MobilePhase B: Ethanol with 0.1% NH₄OH; Flow rate: 4 mL/min; Pressure: 120bars; Temperature: 40° C.; Retention time: 1.20 min. This is the mostpotent NIK enzyme inhibitor among the 4 stereoisomers. The absolutestereo configuration was confirmed by X-ray crystallography of aco-crystal with a protein.

Compound 2:1-(3-(((1S,4R,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide(12.4 mg, 9.3%). LC-MS (ES, m/z): 388 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6)δ 8.78 (dd, J=4.5, 1.7 Hz, 1H), 8.67 (dd, J=8.1, 1.7 Hz, 1H), 8.52-8.45(m, 2H), 8.25 (s, 1H), 7.71 (s, 1H), 7.67-7.60 (m, 1H), 7.51 (dd, J=8.1,4.5 Hz, 1H), 7.45 (dt, J=7.7, 1.3 Hz, 1H), 6.86 (s, 1H), 3.29 (dd,J=4.6, 2.2 Hz, 1H), 2.85 (s, 3H), 1.89 (ddd, J=8.8, 6.7, 4.8 Hz, 1H),1.06 (ddd, J=8.8, 6.0, 4.8 Hz, 1H), 0.52 (ddd, J=6.0, 4.8, 2.3 Hz, 1H).SFC analytical conditions: Instrument: Waters ACQUITY UPC2 System(Waters UPC2); Column: Chiralpak AD (50×4.6 mm, 3 μm); Method: Isocratic(40% Mobile Phase B); Mobile Phase A: carbon dioxide; Mobile Phase B:Ethanol with 0.1% NH₄OH; Flow rate: 4 mL/min; Pressure: 120 bars;Temperature: 40° C.; Retention time: 0.83 min. This is the second mostpotent NIK enzyme inhibitor among the 4 stereoisomers. The absolutestereo configuration was confirmed by X-ray crystallography of aco-crystal with a protein.

1-(3-(((1S,4S,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide(32.3 mg, 24.1%). LC-MS (ES, m/z): 388 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6)δ 8.78 (dd, J=4.6, 1.7 Hz, 1H), 8.67 (dd, J=8.1, 1.7 Hz, 1H), 8.54-8.47(m, 2H), 8.26 (s, 1H), 7.71 (s, 1H), 7.64 (td, J=7.9, 0.8 Hz, 1H), 7.52(dd, J=8.1, 4.5 Hz, 1H), 7.49-7.44 (m, 1H), 6.47 (s, 1H), 3.38-3.33 (m,1H), 2.82 (s, 3H), 2.11-2.01 (m, 1H), 0.86 (ddd, J=8.4, 5.9, 4.8 Hz,1H), 0.64 (ddd, J=5.8, 4.7, 2.4 Hz, 1H). SFC analytical conditions:Instrument: SFC PICLab PREP 100 (PIC 100 SFC); Column: Chiralpak AD(150×21.1 mm, 5 μm); Method: Isocratic (45% Mobile Phase B); MobilePhase A: carbon dioxide; Mobile Phase B: Ethanol with 0.1% NH₄OH; Flowrate: 70 mL/min; Pressure: 100 bars; Temperature: 40° C.; Retentiontime: 1.51 min. This stereoisomer showed no measurable inhibition forthe NIK enzyme. The absolute stereo configuration was confirmed by X-raycrystallography of a single crystal.

1-(3-(((1R,4S,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide(11.3 mg, 8.43%). LC-MS (ES, m/z): 388 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6)δ 8.78 (dd, J=4.5, 1.7 Hz, 1H), 8.67 (dd, J=8.1, 1.7 Hz, 1H), 8.52-8.45(m, 2H), 8.25 (s, 1H), 7.71 (s, 1H), 7.67-7.60 (m, 1H), 7.51 (dd, J=8.1,4.5 Hz, 1H), 7.45 (dt, J=7.7, 1.3 Hz, 1H), 6.86 (s, 1H), 3.29 (dd,J=4.6, 2.2 Hz, 1H), 2.85 (s, 3H), 1.89 (ddd, J=8.8, 6.7, 4.8 Hz, 1H),1.06 (ddd, J=8.8, 6.0, 4.8 Hz, 1H), 0.52 (ddd, J=6.0, 4.8, 2.3 Hz, 1H).SFC analytical conditions: Instrument: SFC PICLab PREP 100 (PIC 100SFC); Column: Chiralpak AD (150×21.1 mm, 5 μm); Method: Isocratic (45%Mobile Phase B); Mobile Phase A: carbon dioxide; Mobile Phase B: Ethanolwith 0.1% NH₄OH; Flow rate: 70 mL/min; Pressure: 100 bars; Temperature:40° C.; Retention time: 1.08 min. This stereoisomer showed no measurableinhibition for the NIK enzyme.

Example 3 Synthesis of3-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1-carboxamide

Step 1: Synthesis of ethyl1-(3-(trimethylsilyl)phenyl)imidazo[1,5-a]pyridine-3-carboxylate

A degassed mixture of 1-bromo-imidazo[1,5-a]pyridine-3-carboxylic acidethyl ester (200 mg, 0.743 mmol), (3-trimethylsilylphenyl)boronic acid(174 mg, 0.896 mmol), 1.0 M aqueous Cs₂CO₃ (0.75 mL, 0.75 mmol) and 1.0M aqueous Cs₂CO₃ (0.75 mL, 0.75 mmol) in acetonitrile (6 mL) was heatedat 80° C. for 3 h in a sealed vial. The mixture was diluted with waterand extracted with ethyl acetate. The organic extracts were washed withwater, brine, dried over MgSO₄ and concentrated. The residue waspurified on a 24 g silica gel column eluting with 0-80% gradient ofethyl acetate in heptane to afford 163 mg (65%) of ethyl1-(3-(trimethylsilyl)phenyl)imidazo[1,5-a]pyridine-3-carboxylate.

Step 2: Synthesis of ethyl1-(3-iodophenyl)imidazo[1,5-a]pyridine-3-carboxylate

Iodochloride, 1 M in dichloromethane (D, 2.4 mL, 2.4 mmol) was added toa solution of ethyl1-(3-trimethylsilylphenyl)imidazo[1,5-a]pyridine-3-carboxylate (163 mg,0.482 mmol) in dichloromethane. The mixture was left for 18 hours,quenched with 5% aqueous Na₂S₂O₅ and extracted with ethyl acetate. Theorganic extracts were washed with water, brine, dried over MgSO₄ andconcentrated. The residue was purified on a 12 g silica gel columneluting with 0-80% gradient of ethyl acetate in heptane to afford 185 mg(97%) of ethyl 1-(3-iodophenyl)imidazo[1,5-a]pyridine-3-carboxylate.LC-MS (ES, m/z): 393 [M+H]⁺.

Step 3: Synthesis of ethyl1-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxylate

The compound was obtained by procedures similar to those described forExamples 1 and 2, Step 1 to afford 147 mg (75%) of ethyl1-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxylate.LC-MS (ES, m/z): 416 [M+H]⁺.

Step 4: Synthesis of1-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide

The compound was obtained by procedures similar to those described forExamples 1 and 2, step 2 to afford 133 mg (97.2%) of the title compoundas a mixture of stereoisomers. The mixture was subjected to a chiral SFCseparation to afford four stereoisomers:

SFC preparative conditions: Instrument: SFC PICLab PREP 100 (PIC 100SFC); Column: Chiralpak OJ (250×21.1 mm, 5 μm); Method: Isocratic (30%Mobile Phase B); Mobile Phase A: carbon dioxide; Mobile Phase B:Methanol with 0.1% NH₄OH; Flow rate: 70 mL/min; Pressure: 100 bars;Temperature: 40° C. The individual stereoisomers are identified by theirrespective physical properties (e.g. NMR data and analytical SFCretention time) and their respective absolute configurations wereassigned based on NIK inhibition potency and relative yield (notconfirmed by X-ray crystallography).

Compound 3:3-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1-carboxamide(25 mg, 18.4%). LC-MS (ES, m/z): 387 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ9.49 (dt, J=7.2, 1.1 Hz, 1H), 8.13 (dt, J=9.3, 1.2 Hz, 1H), 8.06 (td,J=1.7, 0.6 Hz, 2H), 8.03-7.98 (m, 1H), 7.60 (s, 1H), 7.52 (td, J=7.8,0.6 Hz, 1H), 7.43-7.35 (m, 1H), 7.27-7.19 (m, 1H), 7.10-6.99 (m, 1H),6.40 (s, 1H), 3.31 (s, 1H), 2.81 (s, 3H), 2.09-2.01 (m, 1H), 0.89-0.80(m, 1H), 0.67-0.59 (m, 1H). SFC analytical conditions: Instrument:Waters ACQUITY UPC2 System (Waters UPC2); Column: Chiralpak OJ (50×4.6mm, 3 μm); Method: Isocratic (25% Mobile Phase B); Mobile Phase A:carbon dioxide; Mobile Phase B: Methanol with 0.1% NH₄OH; Flow rate: 4mL/min; Pressure: 120 bars; Temperature: 40° C.; Retention time: 0.95min (peak 4). This is the most potent NIK enzyme inhibitor among the 4stereoisomers.

1-(3-(((1S,4R,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide(9.2 mg, 7.2%). Retention time 0.77 min (peak 2). LC-MS (ES, m/z): 387[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.49 (dt, J=7.3, 1.1 Hz, 1H), 8.11(dt, J=9.3, 1.2 Hz, 1H), 8.07 (s, 1H), 8.04 (td, J=1.7, 0.5 Hz, 1H),8.00-7.97 (m, 1H), 7.60 (s, 1H), 7.51 (td, J=7.8, 0.6 Hz, 1H), 7.38 (dt,J=7.7, 1.3 Hz, 1H), 7.25-7.20 (m, 1H), 7.08-7.02 (m, 1H), 6.79 (s, 1H),3.30-3.25 (m, 1H), 2.84 (s, 3H), 1.94-1.84 (m, 1H), 1.11-1.01 (m, 1H),0.55-0.48 (m, 1H). This is the second most potent NIK enzyme inhibitoramong the 4 stereoisomers.

1-(3-(((1S,4S,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide(27.2 mg, 20.0%). Retention time 0.82 min (peak 3). LC-MS (ES, m/z): 387[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.49 (dt, J=7.2, 1.1 Hz, 1H), 8.13(dt, J=9.2, 1.2 Hz, 1H), 8.07 (td, J=1.7, 0.6 Hz, 2H), 8.03-7.98 (m,1H), 7.60 (s, 1H), 7.52 (dt, J=7.8, 0.6 Hz, 1H), 7.39 (dt, J=7.7, 1.3Hz, 1H), 7.27-7.19 (m, 1H), 7.09-7.01 (m, 1H), 6.40 (s, 1H), 3.38-3.31(m, 1H), 2.81 (s, 3H), 2.09-2.02 (m, 1H), 0.89-0.81 (m, 1H), 0.67-0.59(m, 1H). This stereoisomer showed no measurable inhibition for the NIKenzyme.

1-(3-(((1R,4S,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide(8.6 mg, 6.4%). Retention time 0.62 min (peak 1). LC-MS (ES, m/z): 387[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.49 (dt, J=7.2, 1.1 Hz, 1H), 8.11(dt, J=9.3, 1.2 Hz, 1H), 8.07 (s, 1H), 8.04 (td, J=1.7, 0.6 Hz, 1H),8.00-7.97 (m, 1H), 7.60 (s, 1H), 7.51 (td, J=7.8, 0.6 Hz, 1H), 7.38 (dt,J=7.7, 1.3 Hz, 1H), 7.26-7.19 (m, 1H), 7.08-7.02 (m, 1H), 6.79 (s, 1H),3.30-3.25 (m, 1H), 2.84 (s, 3H), 1.93-1.84 (m, 1H), 1.10-1.01 (m, 1H),0.55-0.47 (m, 1H). This is the third most potent NIK enzyme inhibitoramong the 4 stereoisomers.

Example 4 Synthesis of1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-7-methoxyimidazo[1,5-a]pyridine-3-carboxamide

A mixture of stereoisomers was prepared in two steps following the samereaction sequence as Example 3, Step 1 and 2 and using ethyl1-bromo-7-methoxyimidazo[1,5-a]pyridine-3-carboxylate as a startingmaterial in the Step 1. The above mixture was subjected to a chiral SFCseparation to afford four stereoisomers:

SFC preparative conditions: Instrument: SFC PICLab PREP 100 (PIC 100SFC); Column: Chiralpak ID (150×21.1 mm, 5 μm); Method: Isocratic (45%Mobile Phase B); Mobile Phase A: carbon dioxide; Mobile Phase B:Methanol with 0.1% NH₄OH; Flow rate: 70 mL/min; Pressure: 100 bars;Temperature: 40° C. The individual stereoisomers are identified by theirrespective physical properties (e.g. NMR data and analytical SFCretention time) and their respective absolute configurations wereassigned based on NIK inhibition potency and relative yield (notconfirmed by X-ray crystallography).

Compound 4:1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-7-methoxyimidazo[1,5-a]pyridine-3-carboxamide(20.5 mg, 20%). LC-MS (ES, m/z): 417 [M+H]⁺. ¹H N MR (400 MHz, DMSO-d₆)δ 9.38 (dd, J=7.8, 0.7 Hz, 1H), 8.06 (td, J=1.8, 0.6 Hz, 1H), 8.01-7.94(m, 2H), 7.54-7.47 (m, 1H), 7.38-7.31 (m, 1H), 7.25 (dd, J=2.5, 0.8 Hz,1H), 6.80 (dd, J=7.8, 2.5 Hz, 1H), 6.39 (s, 1H), 3.94 (s, 3H), 3.39-3.32(m, 1H), 2.81 (s, 3H), 2.10-1.99 (m, 1H), 0.89-0.80 (m, 1H), 0.66-0.60(m, 1H). SFC analytical conditions: Instrument: Waters ACQUITY UPC2System (Waters UPC2); Column: Chiralpak ID (50×4.6 mm, 3 μm); Method:Isocratic (40% Mobile Phase B); Mobile Phase A: carbon dioxide; MobilePhase B: Methanol with 0.1% NH₄OH; Flow rate: 4 mL/min; Pressure: 120bars; Temperature: 40° C.; Retention time: 1.22 min (peak 3). This isthe most potent NIK enzyme inhibitor among the 4 stereoisomers.

1-(3-(((1S,4S,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-7-methoxyimidazo[1,5-a]pyridine-3-carboxamide(16 mg, 16%). LC-MS (ES, m/z): 417 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ9.38 (dd, J=7.8, 0.7 Hz, 1H), 8.06 (td, J=1.8, 0.6 Hz, 1H), 8.02-7.94(m, 2H), 7.50 (td, J=7.7, 0.6 Hz, 1H), 7.25 (dd, J=2.5, 0.8 Hz, 1H),7.28-7.22 (m, 1H), 6.80 (dd, J=7.8, 2.5 Hz, 1H), 6.39 (s, 1H), 3.94 (s,3H), 3.39-3.32 (m, 1H), 2.81 (s, 3H), 2.10-1.98 (m, 1H), 0.89-0.80 (m,1H), 0.68-0.59 (m, 1H). Retention time 1.33 min (peak 4). Thisstereoisomer showed no measurable inhibition for the NIK enzyme.

1-(3-(((1S,4R,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-7-methoxyimidazo[1,5-a]pyridine-3-carboxamide(15.4 mg, 15%). LC-MS (ES, m/z): 417 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ9.38 (dd, J=7.8, 0.7 Hz, 1H), 8.03 (td, J=1.8, 0.6 Hz, 1H), 7.99-7.94(m, 2H), 7.52-7.46 (m, 2H), 7.35-7.30 (m, 1H), 7.24 (dd, J=2.6, 0.8 Hz,1H), 6.82-6.76 (m, 2H), 3.94 (s, 3H), 3.30-3.27 (m, 1H), 2.84 (s, 3H),1.93-1.83 (m, 1H), 1.09-1.01 (m, 1H), 0.55-0.48 (m, 1H). Retention time0.96 min (peak 1). This is the second most potent NIK enzyme inhibitoramong the 4 stereoisomers.

1-(3-(((1R,4S,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)-7-methoxyimidazo[1,5-a]pyridine-3-carboxamide(10.3 mg, 10%). LC-MS (ES, m/z): 417 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.38 (dd, J=7.8, 0.7 Hz, 1H), 8.03 (td, J=1.8, 0.6 Hz, 1H), 8.01-7.93(m, 2H), 7.54-7.45 (m, 1H), 7.36-7.30 (m, 1H), 7.24 (dd, J=2.6, 0.8 Hz,1H), 6.83-6.76 (m, 2H), 3.94 (s, 3H), 3.29-3.26 (m, 1H), 2.84 (s, 3H),1.93-1.84 (m, 1H), 1.10-1.02 (m, 1H), 0.54-0.47 (m, 1H). Retention time1.05 min (peak 2). This is the third most potent NIK enzyme inhibitoramong the 4 stereoisomers.

Example 5 Synthesis of3-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1-carboxamide

Ethyl3-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1-carboxylatewas prepared in two steps following the same reaction sequence asExample 3, Step 1 and 2 using ethyl3-bromoimidazo[1,5-a]pyridine-1-carboxylate as a starting material inStep 1.

Step 3: Synthesis of1-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxylicacid

A mixture of ethyl1-[3-[2-(2-hydroxy-4-methyl-3-oxo-4-azabicyclo[3.1.0]hexan-2-yl)ethynyl]phenyl]imidazo[1,5-a]pyridine-3-carboxylate(147 mg, 0.354 mmol) and 1 M aqueous LiOH (0.88 mL, 0.88 mmol) inmethanol (4 ml) was stirred for 18 hours. The resulting mixture wasacidified to pH 4 and partitioned between ethyl acetate and brine. Theorganic extracts were dried over MgSO₄ and concentrated giving a cruderesidue of the title compound (170 mg, 100%) which was used withoutfurther purification. LC-MS (ES, m/z): 386 [M−H]⁻, 388 [M+H]⁺.

Step 4: Synthesis of1-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide

HATU (200 mg, 0.526 mmol) was added to a stirred mixture of3-[3-[2-(2-hydroxy-4-methyl-3-oxo-4-azabicyclo[3.1.0]hexan-2-yl)ethynyl]phenyl]imidazo[1,5-a]pyridine-1-carboxylicacid (170 mg, 0.44 mmol), triethylamine (0.327 mL, 2.35 mmol) and finelypowdered ammonium chloride (101 mg, 1.9 mmol) in N,N-dimethylformamide(4 mL). The mixture was stirred for 4 hours. The mixture was dilutedwith water and extracted with ethyl acetate. The organic extracts werewashed with 5% aqueous citric acid, sat. NaHCO₃, water, brine, driedover MgSO₄ and concentrated. The residue was purified on a 4 g silicagel column eluting with methanol gradient in dichloromethane. Collectedfractions give 95 mg (57%) of the title compound as a mixture ofstereoisomers.

The above mixture was subjected to a chiral SFC separation to affordthree of the four stereoisomers:

SFC preparative conditions: Instrument: SFC PICLab PREP 100 (PIC 100SFC); Column: Chiralpak IA (250×21.1 mm, 5 μm); Method: Isocratic (40%Mobile Phase B); Mobile Phase A: carbon dioxide; Mobile Phase B:Methanol with 0.1% NH₄OH; Flow rate: 70 mL/min; Pressure: 100 bars;Temperature: 40° C. The individual stereoisomers are identified by theirrespective physical properties (e.g. NMR data and analytical SFCretention time) and their respective absolute configurations wereassigned based on NIK inhibition potency and relative yield (notconfirmed by X-ray crystallography).

Compound 5:1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide)(12 mg, 12.4%). LC-MS (ES, m/z): 387 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.55 (dt, J=7.2, 1.1 Hz, 1H), 8.21 (dt, J=9.1, 1.3 Hz, 1H), 7.96-7.90(m, 2H), 7.66-7.55 (m, 2H), 7.22-7.13 (m, 2H), 6.97-6.89 (m, 1H), 6.43(s, 1H), 3.34-3.32 (m, 1H), 2.81 (s, 3H), 2.08-2.00 (m, 1H), 0.89-0.80(m, 1H), 0.67-0.59 (m, 1H). Supercritical Fluid Chromatographyanalytical conditions: Instrument: Waters ACQUITY UPC2 System (WatersUPC2); Column: Chiralpak IA (50×4.6 mm, 3 μm); Method: Isocratic (35%Mobile Phase B); Mobile Phase A: carbon dioxide; Mobile Phase B:Methanol with 0.1% NH₄OH; Flow rate: 4 mL/min; Pressure: 120 bars;Temperature: 40° C.; Retention time: 1.17 min (peak 2). This is the mostpotent NIK enzyme inhibitor among the 4 stereoisomers.

3-(3-(((1S,4R,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1-carboxamide(11.6 mg, 12%). LC-MS (ES, m/z): 387 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.54 (dd, J=7.3, 1.1 Hz, 1H), 8.21 (dt, J=9.2, 1.2 Hz, 1H), 7.96-7.89(m, 2H), 7.65-7.54 (m, 2H), 7.22-7.12 (m, 2H), 6.97-6.90 (m, 1H), 6.43(s, 1H), 3.31-3.30 (m, 1H), 2.81 (s, 3H), 2.09-2.00 (m, 1H), 0.89-0.80(m, 1H), 0.66-0.61 (m, 1H). Retention time 1.38 min (peak 3). This isthe second most potent NIK enzyme inhibitor among the 4 stereoisomers.

3-(3-(((1S,4S,5R)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-1-carboxamide(4 mg, 4%). LC-MS (ES, m/z): 387 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.55 (dt, J=7.2, 1.1 Hz, 1H), 8.21 (dt, J=9.1, 1.3 Hz, 1H), 7.96-7.90(m, 2H), 7.65-7.54 (m, 3H), 7.22-7.12 (m, 2H), 6.97-6.90 (m, 1H), 6.43(s, 1H), 3.31-3.29 (m, 1H), 2.81 (s, 3H), 2.08-2.00 (m, 1H), 0.89-0.81(m, 1H), 0.67-0.59 (m, 1H). Retention time 0.98 min (peak 1). This isthe third most potent NIK enzyme inhibitor among the 4 stereoisomers.

Example 6 Synthesis of5-amino-2-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)thiazole-4-carboxamide

Step 1: Synthesis ofmethyl-2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate

A solution of tert-butoxycarbonyl tert-butyl carbonate (476 mg, 2.18mmol) was added dropwise to a suspension of methyl2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylate (633 mg, 1.88mmol), N,N-diisopropylethylamine (0.38 mL, 2.2 mmol) and4-dimethylaminopyridine (25 mg, 0.20463 mmol) in dichloromethane (20ml). The mixture was stirred for 3 hours, concentrated and the residuewas partitioned between ethyl acetate and water. The organic extractswere washed with 5% aqueous citric acid, water, brine, dried over MgSO₄and concentrated. The residue was purified on 12 g silica gel columneluting with iPrOAc gradient in heptane to afford the title compound(633 mg, 94.7%). LC-MS (ES, m/z): 337 [M+H]⁺.

Step 2: Synthesis of methyl5-((tert-butoxycarbonyl)amino)-2-(3-(trimethylsilyl)phenyl)thiazole-4-carboxylate

The title compound was prepared following procedure as Example 3, Step 1and using methyl2-bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate as astarting material to afford 185 mg (73.7%). LC-MS (ES, m/z): 407 [M+H]⁺.

Step 3: Synthesis of methyl5-((tert-butoxycarbonyl)amino)-2-(3-iodophenyl)thiazole-4-carboxylate

The title compound was prepared following procedure as Example 3, Step2, and using methyl5-((tert-butoxycarbonyl)amino)-2-(3-(trimethylsilyl)phenyl)thiazole-4-carboxylateas a starting material to afford 140 mg (66.8%). LC-MS (ES, m/z): 461[M+H]⁺.

Step 4: Synthesis of methyl5-((tert-butoxycarbonyl)amino)-2-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)thiazole-4-carboxylate

The title compound was obtained by procedures similar to those describedfor Examples 1 and 2, Step 1 to afford 112 mg (76.2%) as a mixture ofstereoisomers. LC-MS (ES, m/z): 484 [M+H]⁺.

Step 5: Synthesis of tert-butyl(4-carbamoyl-2-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)thiazol-5-yl)carbamate

The title compound was obtained by a procedure similar to that describedfor Examples 1 and 2, Step 2 to afford 102 mg (94%) as a mixture ofstereoisomers. LC-MS (ES, m/z): 469 [M+H]⁺.

Step 6:5-amino-2-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl) thiazole-4-carboxamide

The title compound was obtained by a deprotection procedure as follows:A solution of hydrogen chloride in dioxane (4 mL, 16 mmol, 4.0 mol/L)was added to a solution oftert-butyl-N-[4-carbamoyl-2-[3-[2-(2-hydroxy-4-methyl-3-oxo-4-azabicyclo[3.1.0]hexan-2-yl)ethynyl]phenyl]thiazol-5-yl]carbamate(102 mg, 0.22 mmol) in 6 ml of dichloromethane. The mixture was stirredfor 1 hour, concentrated and partitioned between saturated aqueousNaHCO₃ and ethyl acetate. The organic extracts were washed with brine,dried over MgSO₄ and concentrated to give 51 mg (63%) of the titlecompound as a mixture of diastereomers. LC-MS (ES, m/z): 369 [M+H]⁺.

The above mixture was subjected to a chiral SFC separation to affordfour stereoisomers:

SFC preparative conditions: Instrument: SFC PICLab PREP 100 (PIC 100SFC); Column: Chiralpak IA (250×21.1 mm, 5 μm); Method: Isocratic (40%Mobile Phase B); Mobile Phase A: carbon dioxide; Mobile Phase B:Methanol with 0.1% NH₄OH; Flow rate: 70 mL/min; Pressure: 100 bars;Temperature: 40° C. The individual stereoisomers are identified by theirrespective physical properties (e.g. NMR data and analytical SFCretention time) and their respective absolute configurations wereassigned based on NIK inhibition potency and relative yield (notconfirmed by X-ray crystallography).

Compound 6:1-(3-(((1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)imidazo[1,5-a]pyridine-3-carboxamide)(8.2 mg, 16%). LC-MS (ES, m/z): 369 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ7.87 (td, J=1.7, 0.6 Hz, 1H), 7.78-7.73 (m, 1H), 7.48-7.37 (m, 5H), 7.07(s, 1H), 6.40 (s, 1H), 3.31-3.29 (m, 1H), 2.81 (s, 3H), 2.06-1.99 (m,1H), 0.89-0.81 (m, 1H), 0.66-0.59 (m, 1H). Supercritical FluidChromatography analytical conditions: Instrument: Waters ACQUITY UPC2System (Waters UPC2); Column: Chiralpak IA (50×4.6 mm, 3 μm); Method:Isocratic (35% Mobile Phase B); Mobile Phase A: carbon dioxide; MobilePhase B: Methanol with 0.1% NH₄OH; Flow rate: 4 mL/min; Pressure: 120bars; Temperature: 40° C.; Retention time 1.01 min (peak 2). This is themost potent NIK enzyme inhibitor among the 4 stereoisomers.

5-amino-2-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)thiazole-4-carboxamide,Peak 4 (3.3 mg, 6.4%). LC-MS (ES, m/z): 369 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 7.87 (td, J=1.7, 0.6 Hz, 1H), 7.78-7.73 (m, 1H), 7.49-7.37(m, 5H), 7.07 (s, 1H), 6.40 (s, 1H), 3.31-3.29 (m, 1H), 2.81 (s, 3H),2.07-2.00 (m, 1H), 0.89-0.80 (m, 1H), 0.66-0.59 (m, 1H). Retention time1.40 min (peak 4). This isomer is a less potent NIK enzyme inhibitorthan Compound 6.

5-amino-2-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)thiazole-4-carboxamide,Peak 1 (3.2 mg, 6.3%). LC-MS (ES, m/z): 369 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 7.85 (td, J=1.8, 0.6 Hz, 1H), 7.77-7.72 (m, 1H), 7.48-7.37(m, 5H), 7.07 (s, 1H), 6.79 (s, 1H), 3.30-3.26 (m, 2H), 2.83 (s, 3H),1.90-1.82 (m, 1H), 1.09-1.00 (m, 1H), 0.55-0.48 (m, 1H). Retention time0.85 min (peak 1). This isomer is a less potent NIK enzyme inhibitorthan Compound 6.

5-amino-2-(3-((4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl)ethynyl)phenyl)thiazole-4-carboxamide,Peak 3 (3.9 mg, 7.7%). LC-MS (ES, m/z): 369 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 7.85 (td, J=1.8, 0.6 Hz, 1H), 7.77-7.72 (m, 1H), 7.47-7.37(m, 5H), 7.07 (s, 1H), 6.79 (s, 1H), 3.30-3.26 (m, 1H), 2.83 (s, 3H),1.91-1.82 (m, 1H), 1.08-1.00 (m, 1H), 0.54-0.48 (m, 1H). Retention time1.08 min (peak 3). This isomer is a less potent NIK enzyme inhibitorthan Compound 6.

BIOLOGICAL EXAMPLES Example B1—NIK Enzyme Inhibition Assay

The ability of the nuclear factor-kappa B (NF-kB)-inducing kinase (NIK)to catalyze the hydrolysis of adenosine-5′-triphosphate (ATP) wasmonitored using the Transcreener ADP (adenosine-5′-diphosphate) assay(BellBrook Labs). Purified NIK (0.5 nM) derived from abaculovirus-infected insect cell expression system was incubated withtest compounds for 1-3.5 hours in 50 mM2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid buffer (pH 7.2)containing 10 mM MgCl₂, 2 mM dithiothreitol, 10 μM ATP, 0.01% TritonX-100, 0.1% gamma-globulins from bovine blood, 1% dimethylsulfoxide(DMSO), 7 μg/mL ADP antibody and 5 nM ADP-MR121 633 tracer. Reactionswere quenched by the addition of 20 mM2,2′,2″,2′″-(ethane-1,2-diyldinitrilo)tetraacetic acid and 0.01% Brij35. The tracer bound to the antibody was displaced by the ADP generatedduring the NIK reaction, which causes a decrease in fluorescencepolarization that was measured by laser excitation at 633 nm with aFluorescence Correlation Spectroscopy Plus reader (Evotec AG).Equilibrium dissociation constant (K_(i)) values for NIK inhibitors arecalculated from plots of activity vs. inhibitor concentration usingMorrison's quadratic equation that accounts for the potential of tightbinding, and by also applying the conversion factor that accounted forcompetitive inhibition and the concentration of substrate used in theassay relative to its Michaelis constant (K_(m)). The inhibitory values(NIK ADP-FP, K_(i)) obtained are listed in Table B1.

TABLE B1 Compound No. NIK ADP-FP K_(i) (nM) 1 0.88 2 4.3 3 0.050 4 0.0505 4.7 6 0.050 C-1 0.17 C-3 0.095 C-4 0.050 C-5 4.7 C-6 0.13

Example B2—Cellular Assay

Several assays were developed to profile the cellular activities of NIKinhibitors.

(1) The first assay that can be used to profile whether a test compoundcan inhibit the NF-kB signal through NIK inhibition without affectingcell viability. In this assay, human embryonic kidney 293 cells arestably transfected with a tetracycline-inducible NIK DNA constructcontaining a cytomegalovirus promoter plus two reporter DNA constructs.One reporter encodes firefly luciferase under the control of threerepeats of an NF-kB response element from the ELAM-1 gene and reflectsthe level of NIK activity in the cells, whereas the other reporterconstitutively expresses Renilla luciferase under the control of theherpes simplex virus thymidine kinase promoter and serves as a generalmeasure of cell viability. Cells are incubated with differentconcentrations of compounds (0.2% DMSO final) in medium containing 1μg/mL doxycycline and 10% tet-system approved fetal bovine serum(Clontech) for 24 hours, after which the reporters' signals are detectedusing the Dual Glo luciferase detection system (Promega) according tothe vendor's protocol.

(2) A second set of cell assays used primary human umbilical vein cells(HUVEC) sourced from Lonza to define the selectivity of NIK inhibitorstoward inhibition of classical vs. non-classical NF-kB signaling usinghigh content cellular imaging. For the p52 (non-classical NF-kBsignaling) nuclear translocation assay, HUVEC were treated withdifferent concentrations of compounds (0.2% DMSO final) in EBM-2 medium(LONZA) containing 2% fetal bovine serum and then stimulated with 300ng/mL of an anti-lymphotoxin beta receptor antibody (R&D Systems) for4.5 hours. In the REL-A nuclear translocation assay, HUVEC wereincubated with compounds (0.2% DMSO final) for 4 hours 50 minutes inEBM-2 medium containing 2% fetal bovine serum before stimulating themwith 2 ng/mL tumor necrosis factor (TNF)-α (R&D Systems) for 10 minutes.Cells were fixed with 4% paraformaldehyde, permeabilized by adding 0.1%Triton X-100 in phosphate buffered saline, and then were incubated witheither 2 μg/mL anti-p52 antibody (Millipore) or 400 ng/mL anti-REL-A(p65) antibody (Santa Cruz Biotechnology). Finally, the cells wereincubated with an Alexa488-labeled secondary antibody (Invitrogen) andDRAQ5 DNA stain (Biostatus). Imaging was carried out using an Operareader (Perkin Elmer) and data were analyzed with the aid of Acapellasoftware (Perkin Elmer). The p52 or REL-A translocation into the nucleuswas quantified by the ratio of the nuclear to cytoplasmic signalintensity. The concentration of inhibitor required for 50% inhibition(IC50 values) in these cell assays were derived from the plots of signalvs. inhibitor concentration.

(3) A third set of cell assays are used to define the selectivity of NIKinhibitors toward inhibition of classical vs. non-classical NF-kBsignaling and rely on quantification of the nuclear translocation of p52(NF-kB2) and REL-A (p65) using high content cellular imaging. For thep52 (non-classical NF-kB signaling) nuclear translocation assay, HeLacells are treated with different concentrations of compounds (0.2% DMSOfinal) in medium containing 10% fetal bovine serum and then stimulatedwith 100 ng/mL of an anti-lymphotoxin beta receptor antibody (R&DSystems) for 5 hours. In the REL-A nuclear translocation assay, HeLacells are incubated with compounds (0.2% DMSO final) for 4.5 hours inmedium containing 10% fetal bovine serum before stimulating them with 10ng/mL tumor necrosis factor (TNF)-α (R&D Systems) for 30 minutes. Cellsare fixed with 4% paraformaldehyde, permeabilized by adding 0.1% TritonX-100 in phosphate buffered saline, and then are incubated with either 2μg/mL anti-p52 antibody (Millipore) or 400 ng/mL anti-REL-A (p65)antibody (Santa Cruz Biotechnology). Finally, the cells are incubatedwith an Alexa488-labeled secondary antibody (Invitrogen) and DRAQ5 DNAstain (Biostatus). Imaging is carried out using an Opera reader (PerkinElmer) and data are analyzed with the aid of Acapella software (PerkinElmer). The p52 or REL-A translocation into the nucleus is quantified bythe ratio of the nuclear to cytoplasmic signal intensity. Theconcentration of inhibitor required for 50% inhibition (IC₅₀ values) inthese cell assays are derived from the plots of signal vs. inhibitorconcentration. The test compounds have the corresponding inhibitoryvalues (IC₅₀) for NIK REL-A (p65) and p52 Translocation Assays as setforth in Table B2.

TABLE B2 REL-A REL-A p52 p52 HUVEC HeLa HUVEC HeLa Trans- Trans- Trans-Trans- location location location location Compound Assay Assay AssayAssay No. (IC₅₀) [μM] (IC₅₀) [μM] (IC₅₀) [μM] (IC₅₀) [μM] 1 >5 0.0552 >5 0.28 3 >5 0.025 5 >5 3 C-1 >20 0.0795 C-3 >5 >20 0.0298 C-4 >5 >1.00.0066 C-5 >20 0.2399 C-6 >5.0 0.0791

Example B3—Liver Microsome Stability

General.

Metabolic stability assays in liver microsomes are conducted with pooledfemale CD-1 mouse, male Sprague-Dawley rat, male beagle dog, malecynomolgus monkey, and mixed male and female human liver microsomalincubations. The general assay conditions are as follows. Incubationmixtures consisted of liver microsomes (0.5 mg of microsomal protein/ml)and the test compound (1.0 μM) with or without NADPH (1.0 mM) in thepotassium phosphate buffer (100 mM; pH 7.4) with a final incubationvolume of 0.25 ml. Reactions are initiated by the addition of NADPH orbuffer and shaken in a water bath open to the air at 37° C. At times 0,20, 40, and 60 min, aliquots (50 μl) are removed and added totermination mixtures (100 μl) containing acetonitrile and an internalstandard. The samples are then centrifuged for 10 min at 2000 g. Thesupernatant (90 μl) is removed, combined with 180 μl of water, andanalyzed by LC-MS/MS.

Metabolic stability of the test compounds were evaluated in human livermicrosomes following known protocols described in Halladay, et al. DrugMetabol. Lett. 2007, 1:67-72.

The human liver microsome clearance (HLM CL, in mL/min/kg) obtained forthe test compounds are shown in Table B3. A lower clearance valueindicates better metabolic stability. Compound Nos. 1, 3, 4, 5 and 6 ineach case showed better stability in human liver microsomes than therespective comparator compounds C-1, C-3, C-4, C-5 and C-6. Also seeFIG. 1.

TABLE B3 Compound No. HLM CL (mL/min/kg) 1 5.8 2 7.7 3 11 4 12 5 3.5 61.6 C-1 7.4 C-3 13 C-4 15 C-5 4.0 C-6 5.1

Example B4—Hepatocyte Stability

General. Metabolic stability assays in hepatocytes are conducted usingcryopreserved pooled female CD-1 mouse, male Sprague-Dawley rat, malebeagle dog, male cynomolgus monkey, and mixed male and female humanhepatocytes (CellzDirect). Vials of hepatocytes are thawed rapidly in awater bath set at 37° C. and then are diluted with Dulbecco's modifiedEagle's medium (DMEM), pH 7.4. Cells are isolated by centrifugation,pooled, and resuspended in DMEM at 1.0 million viable cells/ml. Membraneintegrity of the cells is assessed by trypan blue exclusion. The testcompound is dissolved in dimethyl sulfoxide at a final concentration of10 mM. This test compound stock is diluted further to 2 μM in DMEM (125μl) before the addition of an equal volume of the 10⁶ cells/ml cellsuspension. The test compound (final incubation concentration of 1.0 μMwith 0.1% dimethyl sulfoxide) and cells (final concentration of 0.5×10⁶cells/ml) are incubated at 37° C. in a 95% air/5% CO₂ atmosphere for 3h. Aliquots (50 μl) are removed at 0, 1, 2, and 3 hours and added totermination mixtures (100 μl) containing acetonitrile and an internalstandard. The samples are then centrifuged for 10 min at 2000 g. Thesupernatant (90 μl) is removed, combined with 180 μl of water, andanalyzed by LC-MS/MS.

Metabolic stability of the test compounds were evaluated also in humanhepatocytes, following protocols described in Hallifax, et al. DrugMetabol. Disposition, 2005, 33:1852-1858.

The human hepatocyte clearance (Hep CL, in mL/min/kg) obtained for thetest compounds are shown in Table B4. A lower clearance value indicatesbetter metabolic stability. Compound Nos. 1, 3 and 5 show betterstability than the corresponding comparator compounds C-1, C-3 and C-5respectively in the human hepatocyte assay. A greater improvement isshown for 2-azabicyclo[3.1.0]hexan-3-one compounds in cases where thecorresponding pyrrolidinone compounds have a relatively high clearance.Also see FIG. 2.

TABLE B4 Compound No. Hep CL (mL/min/kg) 1 0.8 2 13 3 9.0 4 N.D. 5 1.6 62.7 C-1 9.5 C-3 14 C-4 9.9 C-5 2.5 C-6 1.1

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

The invention claimed is:
 1. A compound of formula (A):

or a stereoisomer, tautomer, solvate, or pharmaceutically acceptablesalt thereof, wherein: ring A is a monocycle or a fused bicycle; A₁ isNR¹, N, S, CR¹ or CHR¹; A₂ is NR², N, O, S, CR² or CHR²; A₃ is N or C;provided that no more than two of (i)-(iii) apply: (i) A₁ is NR¹ or N,(ii) A₂ is NR² or N, and (iii) A₃ is N; each R¹ is independentlyselected from the group consisting of H, halogen, —NR^(a)R^(b),—NHC(O)NR^(a)R^(b), —NHS(O)₂—C₁-C₃ alkyl, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,C₁-C₃ alkoxy and 3-11 membered heterocyclyl, wherein the C₁-C₃ alkyl ofR¹ is optionally substituted by F, OH, CN, SH, C₁-C₃ alkoxy or 3-11membered heterocyclyl; the C₃-C₇ cycloalkyl of R¹ is optionallysubstituted by F, OH, CN, SH, CH₃ or CF₃; the C₁-C₃ alkoxy of R¹ isoptionally substituted by F, OH, CN or SH; and the 3-11 memberedheterocyclyl of R¹ is optionally substituted by F, OH, CN, SH, CF₃ orC₁-C₃ alkyl; each R² is independently selected from the group consistingof H, NR^(a)R^(b), C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, phenyland 3-11 membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ alkoxy, phenyl and 3-11 membered heterocyclyl of R² isoptionally substituted by R^(c); or R¹ and R² are taken together withthe atoms to which they are attached to form a cyclic group selectedfrom the group consisting of C₃-C₇ cycloalkyl, phenyl and 3-11 memberedheterocyclyl, wherein the cyclic group is optionally substituted byR^(d); each R^(4a) and R^(4b) is independently H or F; R⁵ is C₁-C₆ alkylor C₃-C₄ cycloalkyl, wherein the C₁-C₆ alkyl and C₃-C₄ cycloalkyl of R⁵are independently optionally substituted by halogen, OH, or C₁-C₆alkoxy; each R⁶ is independently selected from the group consisting ofF, Cl, OCH₃, CH₃ and CF₃; n is 0, 1 or 2, R^(a) is selected from thegroup consisting of H and C₁-C₆ alkyl optionally substituted by C₁-C₃alkoxy, F, OH, CN, SH, CH₃ or CF₃; R^(b) is selected from the groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, C(O)R^(g),phenyl and 3-11 membered heterocyclyl wherein R^(b) may be optionallysubstituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃; R^(c) and R^(d)are each independently selected from the group consisting of halogen,—(X¹)₀₋₁—CN, —(X¹)₀₋₁—NO₂, —(X¹)₀₋₁—SF₅, —(X¹)₀₋₁—NH₂,—(X¹)₀₋₁—N(H)(R^(1a)), —(X¹)₀₋₁—N(R^(1b))(R^(1a)), C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, oxo,—(X¹)₀₋₁—C₁-C₆ alkyl, —(X′)₀₋₁—C₃-C₁₀ cycloalkyl, cycloalkyl,—(X¹)₀₋₁-3-11 membered heterocyclyl, —(X¹)₀₋₁-C₆-C₁₀ aryl,—C(═O)(X¹)₀₋₁-C₃-C₁₀ cycloalkyl, —C(═O)(X¹)₀₋₁—3-11 memberedheterocyclyl, —(X¹)₀₋₁-C(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁-C(═Y¹)NH₂,—(X¹)₀₋₁—C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁-C(═Y¹)OR^(1a),—(X¹)₀₋₁—C(═Y¹)OH, —(X¹)₀₋₁—N(H)C(═Y¹)(R^(1a)),—(X¹)₀₋₁—N(R^(1b))C(═Y¹)(R^(1a)), —(X¹)₀₋₁—N(R^(1b))C(═Y¹)(H),—(X¹)₀₋₁—N(H)C(═Y¹)OR^(1a), —(X¹)₀₋₁—N(R^(1b))C(═Y¹)OR^(1a),—(X¹)₀₋₁—S(O)₁₋₂R^(1a), —(X¹)₀₋₁—N(H)S(O)₁₋₂R^(1a),—(X¹)₀₋₁—N(R^(1b))S(O)₁₋₂R^(1a), —(X¹)₀₋₁—S(O)₀₋₁N(H)(R^(1a)),—(X¹)₀₋₁—S(O)₀₋₁N(R^(1b))(R^(1a)), —(X¹)₀₋₁—S(O)₀₋₁NH₂,—(X¹)₀₋₁—S(═O)(═NR^(1b))R^(1a), —(X¹)₀₋₁—C(═Y¹)R^(1a), —(X¹)₀₋₁—C(═Y¹)H,—(X¹)₀₋₁-C(═NOH)R^(1a), —(X¹)₀₋₁—C(═NOR^(1b))R^(1a),—(X¹)₀₋₁—NHC(═Y¹)N(H)(R^(1a)), —(X¹)₀₋₁—NHC(═Y¹)NH₂,—(X¹)₀₋₁—NHC(═Y¹)N(R^(1b))(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(H)(R^(1a)),—(X¹)₀₋₁—N(R^(1a))C(═Y¹)N(R^(1a))(R^(1b)), —(X¹)₀₋₁—N(R^(1a))C(═Y¹)NH₂,—(X¹)₀₋₁—OC(═Y¹)R^(1a), —(X¹)₀₋₁—OC(═Y¹)H, —(X¹)₀₋₁—OC(═Y¹)OR^(1a),—(X¹)₀₋₁—OP(═Y¹)(OR^(1a))(OR^(1b)), —(X¹)—SC(═Y¹)OR^(1a) and—(X¹)—SC(═Y¹)N(R^(1a))(R^(1b)); wherein X¹ is selected from the groupconsisting of C₁-C₆ alkylene, C₁-C₆ heteroalkylene, C₂-C₆ alkenylene,C₂-C₆ alkynylene, C₁-C₆ alkyleneoxy, C₃-C₇ cycloalkylene, 3-11 memberedheterocyclylene and phenylene; R^(1a) and R^(1b) are each independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkylene)C₁-C₆ alkyl,3-11 membered heterocyclyl, (3-11 membered heterocyclylene)C₁-C₆ alkyl,phenyl, and (C₆-C₁₀ arylene)C₁-C₆ alkyl, or R^(1a) and R^(1b), whenattached to the same nitrogen atom, are taken together with the nitrogento which they are attached to form a 3-11 membered heterocyclylcomprising 0-3 additional heteroatoms selected from N, O and S; Y¹ is O,NR^(1c) or S wherein R^(1c) is H or C₁-C₆ alkyl; wherein any portion ofan R^(c) or R^(d) substituent, including R^(1a), R^(1b) and R^(1c), ateach occurrence is independently further substituted by from 0 to 4R^(f) substituents selected from the group consisting of halogen, CN,NO₂, SF₅, OH, NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), oxo, C₁-C₆ alkyl,—(C₂-C₆ alkynylene)-(3-11 membered heterocyclyl, wherein theheterocyclyl is optionally substituted by R^(e)), C₁-C₆ hydroxyalkyl,C₁-C₆ heteroalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl, 3-11membered heterocyclyl, —C(═O)N(H)(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂,—C(═O)NH₂, —C(═O)OC₁-C₆ alkyl, —C(═O)OH, —N(H)C(═O)(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(═O)(C₁-C₆ alkyl), —N(H)C(═O)OC₁-C₆ alkyl, —N(C₁-C₆alkyl)C(═O)OC₁-C₆ (halo)alkyl, —S(O)₁₋₂C₁-C₆ alkyl, —N(H)S(O)₁₋₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₁₋₂C₁-C₆ alkyl, —S(O)₀₋₁N(H)(C₁-C₆ alkyl),—S(O)₀₋₁N(C₁-C₆ alkyl)₂, —S(O)₀₋₁NH₂, —C(═O)C₁-C₆ alkyl, —C(═O)C₃-C₇cycloalkyl, —C(═NOH)C₁-C₆ alkyl, —C(═NOC₁-C₆ alkyl)C₁-C₆ alkyl,—NHC(═O)N(H)(C₁-C₆ alkyl), —NHC(═O)N(C₁-C₆ alkyl)₂, —NHC(═O)NH₂,—N(C₁-C₆ alkyl)C(═O)N(H)(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(═O)NH₂,—OC(═O)C₁-C₆ alkyl, —OC(═O)OC₁-C₆ alkyl, —OP(═O)(OC₁-C₆ alkyl)₂,—SC(═O)OC₁-C₆ alkyl and —SC(═O)N(C₁-C₆ alkyl)₂, wherein any alkylportion of R^(f) is optionally substituted with halogen; R^(e) isselected from the group consisting of halogen, OH, C₁-C₆ alkyl and oxo;and R^(g) is selected from the group consisting of C₁-C₆ alkyl and C₃-C₆cycloalkyl wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl of R^(g) may beoptionally substituted by C₁-C₃ alkoxy, F, OH, CN, SH, CH₃ or CF₃. 2.The compound of claim 1, or a stereoisomer, tautomer, solvate, prodrugor pharmaceutically acceptable salt thereof, wherein A₁ is NR′ or CR¹.3. The compound of claim 1, or a stereoisomer, tautomer, solvate,prodrug or pharmaceutically acceptable salt thereof, wherein A₂ is NR²,S or CR².
 4. The compound of claim 1, or a stereoisomer, tautomer,solvate, prodrug or pharmaceutically acceptable salt thereof, whereinring A is a monocycle.
 5. The compound of claim 4, or a stereoisomer,tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof,wherein A₁ is CR¹, A₂ is S, and A₃ is C.
 6. The compound of claim 5, ora stereoisomer, tautomer, solvate, or pharmaceutically acceptable saltthereof, wherein R¹ is NH₂.
 7. The compound of claim 4, or astereoisomer, tautomer, solvate, or pharmaceutically acceptable saltthereof, wherein A₁ is CR¹, A₂ is NR², and A₃ is C.
 8. The compound ofclaim 1, or a stereoisomer, tautomer, solvate, or pharmaceuticallyacceptable salt thereof, wherein ring A is a fused bicycle.
 9. Thecompound of claim 8, or a stereoisomer, tautomer, solvate, orpharmaceutically acceptable salt thereof, wherein A₁ is NR¹ or CR¹, A₂is NR² or CR², and R¹ and R² are taken together with the atoms to whichthey are attached to form a 3-11 membered heterocyclyl optionallysubstituted by R^(d).
 10. The compound of claim 9, or a stereoisomer,tautomer, solvate, or pharmaceutically acceptable salt thereof, whereinA₁ is CR¹, A₂ is CR² and A₃ is N.
 11. The compound of claim 9, or astereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptablesalt thereof, wherein A₁ is NR¹, A₂ is CR² and A₃ is C.
 12. The compoundof claim 9, or a stereoisomer, tautomer, solvate, prodrug orpharmaceutically acceptable salt thereof, wherein A₁ is CR¹, A₂ is NR²and A₃ is C.
 13. The compound of claim 9, or a stereoisomer, tautomer,solvate, or pharmaceutically acceptable salt thereof, wherein ring A isselected from the group consisting of:

wherein each m is independently 0, 1, 2 or
 3. 14. The compound of claim9, or a stereoisomer, tautomer, solvate, or pharmaceutically acceptablesalt thereof, wherein ring A is selected from the group consisting of:


15. The compound of claim 1, or a stereoisomer, tautomer, solvate, orpharmaceutically acceptable salt thereof, wherein A₇ is CR⁶ where R⁶ isH.
 16. The compound of claim 15, or a stereoisomer, tautomer, solvate,or pharmaceutically acceptable salt thereof, wherein Ag is CR⁶ where R⁶is H or F.
 17. The compound of claim 16, or a stereoisomer, tautomer,solvate, prodrug or pharmaceutically acceptable salt thereof, wherein A₅is CR⁶ where R⁶ is H.
 18. The compound of claim 17, or a stereoisomer,tautomer, solvate, or pharmaceutically acceptable salt thereof, whereinA₆ is CR⁶ where R⁶ is selected from the group consisting of H, F, OCH₃and CH₃.
 19. The compound of claim 1, or a stereoisomer, tautomer,solvate, or pharmaceutically acceptable salt thereof, wherein thecompound is of the formula (Aa):


20. The compound of claim 1, or a tautomer, solvate, or pharmaceuticallyacceptable salt thereof, wherein the compound is of the formula (Aa-1):


21. The compound of claim 1, or a tautomer, solvate, or pharmaceuticallyacceptable salt thereof, wherein the compound is of the formula (Aa-2):


22. The compound of claim 1, or a stereoisomer, tautomer, solvate,prodrug or pharmaceutically acceptable salt thereof, wherein each R^(4a)and R^(4b) is H.
 23. The compound of claim 1, or a stereoisomer,tautomer, solvate, or pharmaceutically acceptable salt thereof, whereinR⁵ is methyl.
 24. A compound of formula (C):

or a stereoisomer, tautomer, solvate, or pharmaceutically acceptablesalt thereof, wherein: ring A is a monocycle or a fused bicycle; A₁ isNR¹ or CR¹; A₂ is NR², S or CR²; A₃ is N or C; provided that no morethan one of (i)-(iii) applies: (i) Ai is NW¹, (ii) A₂ is NR², and (iii)A₃ is N; each R¹ is independently —NR^(a)R^(b); C₁-C₃ alkyl optionallysubstituted by F, OH, CN, SH or C₁-C₃ alkoxy; or taken together with R²,where present, and the atoms to which they are attached to form a6-membered heterocyclyl optionally substituted by R^(d); each R² isindependently absent or taken together with R¹ and the atoms to whichthey are attached to form a 6-membered heterocyclyl optionallysubstituted by R^(d); n is 0 or 1; R⁶, where present, is halo; eachR^(a) and R^(b) is independently selected from the group consisting of Hand C₁-C₆ alkyl; and each R^(d) is independently selected from the groupconsisting of C₁-C₆ alkyl optionally substituted by halogen and C₁-C₆alkoxy optionally substituted by halogen.
 25. The compound of claim 24,or a stereoisomer, tautomer, solvate, or pharmaceutically acceptablesalt thereof, wherein the compound is of the formula (D):


26. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition comprising a compound of claim 1, or a stereoisomer,tautomer, solvate or, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier, diluent or excipient.
 29. Amethod for the treatment of an inflammatory condition or a fibroticcondition in a patient, comprising administering an effective amount ofa compound of claim 1, or a stereoisomer, tautomer, solvate, prodrug orsalt thereof, to the patient.
 30. The method of claim 29, wherein theinflammatory condition is selected from the group consisting of lupus,systemic lupus erythematosus, chronic obstructive pulmonary disease(COPD), rhinitis, multiple sclerosis, inflammatory bowel disease (IBD),arthritis, rheumatoid arthritis, dermatitis, endometriosis andtransplant rejection.
 31. A method of making a compound of formula (A):

wherein A₁-A₃, R^(4a), R^(4b), R⁵, R⁶, and n are as defined in claim 1,comprising (i) reacting a compound of formula (A-1):

wherein X is —Cl, —Br, —I, —OS(O)₂CF₃, —OC(O)CH₃, —OS(O)₂CH₃,—OS(O)₂(4-CH₃C₆H₄), or —N₂ ⁺; and LG is a leaving group; with a compoundof formula (A-2):

to form a compound of formula (A-3):

(ii) converting the compound of formula (A-3) to the compound of formula(A).
 32. The method of claim 31, further comprising: (i) reacting acompound of formula (A-4):

with bis(trimethylsilyl)peroxide to form a compound of formula (A-5):

and (ii) converting the compound of formula (A-5) to the compound offormula (A-2).
 33. A method of making a compound of formula (C):

wherein A₁, A₂, A₃, R⁶ and n are as defined in claim 24, comprising: (i)reacting a compound of formula (C-1):

wherein X is —C₁, —Br, —I, —OS(O)₂CF₃, —OC(O)CH₃, —OS(O)₂CH₃,—OS(O)₂(4-CH₃C₆H₄), or —N₂ ⁺; and LG is a leaving group; with a compoundof formula (C-2):

to form a compound of formula (C-3):

and (ii) converting the compound of formula (C-3) to the compound offormula (C).
 34. The method of claim 33, further comprising: (i)reacting a compound of formula (1):

with bis(trimethylsilyl)peroxide to form a compound of formula (2):

and (ii) converting the compound of formula (2) to the compound offormula (C-2).